Substituted 1,4-benzodiazepines and uses thereof

ABSTRACT

The present invention is directed to novel 1,4-benzodiazepines, pharmaceutical compositions thereof, and the use thereof as inhibitors of HDM2-p53 interactions. Compounds have Formula I:  
                 
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:  
     X and Y are independently —C(O)—, —CH 2 — or —C(S)—;  
     R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R b , R c , R d  and M arm defined herein;  
     R 5  is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl or alkylaminocarbonylalkyl;  
     R 6  is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, each of which is optionally substituted;  
     R 9  is cycloalkyl: aryl, heteroaryl, a saturated or partially unsaturated heterocycle, cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which is optionally substituted; and  
     R 10  is —(CH 2 ) n —CO 2 R b , —(CH 2 ) m —CO 2 M, —(CH 2 ) i —OH or —(CH 2 ) j —CONR c R d  n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

This application claims priority under 35 U.S.C. § 119(c) to U.S.Provisional Application No. 60/331,235, filed Nov. 13, 2001, which isfully incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is in the area of novel 1,4-benzodiazepines andsalts thereof, their syntheses, and their use as inhibitors of MDM2 andHDM2 oncoproteins.

2. Related Art

This invention relates to compounds that bind to the human protein HDM2and interfere with its interaction with other proteins, especially thetumor suppressor protein p53. HDM2 is the expression of hdm2, anoncogene that is overexpressed in a variety of cancers, especially softtissue sarcomas (Momand, J. et al., Nucl. Acids Res. 26:345-3459(1998)).

p53 is a transcription factor that plays a pivotal role in theregulation of the balance between cell proliferation and cell growtharrest/apoptosis. Under normal conditions, the half-life of p53 is veryshort, and consequently the level of p⁵³ in cells is low. However, inresponse to cellular DNA damage, cellular stress, or other factors,levels of p53 increase. This increase in p53 levels in turn increasesthe transcription of a number of genes which induces the cell to eitherarrest growth or undergo apoptosis (i.e., controlled cell death). Thefunction of p53 is to prevent the uncontrolled proliferation of cellsand thus protect the organism from the development of cancer (for areview, see Levine, A. J., Cell 88:323-331 (1997)).

p53 is a latent and short-lived transcription factor which is inducedby, and is an integration point for, a range of cellular stressesincluding DNA damage, UV damage, spindle damage, hypoxia, inflammatorycytokines, viral infection, activated oncogenes, and ribonucleotidedepletion. Activation of p53 mediates a change in the balance of geneexpression such that expression of many genes involved in proliferationis repressed while a range of genes involved in growth arrest (such asp21WAF1 and GADD45), repair (such as p53RE) and apoptosis (such as Bax,Killer/DR5 and PIGs) is activated. The biological outcome of p53activation (whether permanent or transient growth arrest or apoptosis)is dependent on several factors including the type and strength of theinducing stress, and the type of cell or tissue.

p53 and MDM2 exist in a negative regulatory feedback loop in which p53stimulates transcription of the mdm2 gene while MDM2 binds to p53 andtargets it for degradation by the 26S proteosome. The key element in thep53 induction process is disruption of the p53-MDM2 complex whichpermits p53 to accumulate in the nucleus. This mechanism appears to becommon to all of the pathways by which p53 becomes activated, althoughrecent evidence has indicated that there is considerable variation inthe molecular events by which this is actually achieved.

Inactivation of the p53 tumor suppressor is a frequent event in humanneoplasia. The inactivation can occur by mutation of the p53 gene orthrough binding to viral or cellular oncogene proteins, such as the SV40large T antigen and MDM2. While the mechanism through which wild-typep53 suppresses tumor cell growth is as yet poorly defined, it is clearthat one key feature of the growth suppression is the property of p53 toact as a transcription factor (Farmer, G., et al., Nature 358: 83-86(1992); Funk. W. D. et al., Mol. Cell. Biol. 12: 2866-2871 (1992); Kern,S. E., et al., Science 256:827-830 (1992)). Currently, considerableeffort is being made to identify growth control genes that are regulatedby p53 binding to sequence elements near or within these genes. A numberof such genes have been identified. In cases such as the muscle creatinekinase gene (Weintraub, H., et al, Proc. Natl. Acad. Sci. USA.,88:4570-4571 (1991); Zambetti, G. P., et al, Genes Dev. 6:1143-1152(1992)) and a GLN retroviral element (Zauberman, A., et al., EMBO J.12:2799-2808 (1993)), the role these genes might play in the suppressionof growth control is unclear. Yet there are other examples, namely mdm2(Barak, Y., et al. EMBO J. 12:461-468 (1993); Wu, X., et al., Genes Dev.7:1126-1132(1993)) GADD 45 (Kastan, M. B., et al. Cell 71:587-597(1992))and WAF1 or CIP1 (El-Beiry, W. S., et al., Cell 75:817-825 (1993);Harper, J. W., et al., Cell 75:805-816 (1993)), where their involvementin the regulation of cell growth is better understood.

mdm2, a known oncogene, was originally found on mouse double minutechromosomes (Cahilly-Snyder., L., et al, Somatic Cell Mol. Genet.13:235-244 (1987)). Its protein product was subsequently found to form acomplex with p53, which was first observed in a rat fibroblast cell line(Clone 6) previously transfected with a temperature sensitive mouse p53gene (Michalovitz, D., et al., Cell 62:671-680 (1990)). The rat cellline grew well at 37° C. but exhibited a G1 arrest when shifted down to32° C., which was entirely consistent with an observed temperaturedependent switch in p53 conformation and activity. However, the p53-MDM2complex was only observed in abundance at 32° C., at which temperaturep53 was predominantly in a functional or “wild-type” form (Barak, Y. etal., EMBO J. 11:2115-2121 (1992) and Momand, J., et al., Cell69:1237-1245 (1992)). By shifting the rat cell line down to 32° C. andblocking de novo protein synthesis it was shown that only “wild-type”p53 induced expression of the mdm2 gene, thereby accounting for thedifferential abundance of the complex in terms of p53 transcriptionalactivity (Barak, Y., et al, EMBO J. 12:4614 (1993)). The explanation wasfurther developed by the identification of a DNA binding site forwild-type p53 within the first intron of the mdm2 gene (Wu, X., et al.,Genes Dev. 7:1126-1132 (1993)). Reporter constructs employing this p53DNA binding site revealed that they were inactivated when wild-type p53was co-expressed with MDM2.

This inhibition of the transcriptional activity of p53 may be caused byMDM2 blocking the activation domain of p53 and/or the DNA binding site.Consequently, it was proposed that mdm2 expression is autoregulated, viathe inhibitory effect of MDM2 protein on the transcriptional activity ofwild-type p53. This p53-mdm2 autoregulatory feedback loop provided anovel insight as to how cell growth might be regulated by p53. Up to athird of human sarcomas are considered to overcome p53-regulated growthcontrol by amplification of the hdm2 gene (the human homologue of mdm2)(Oliner, J. D., et al., Nature 358:80-83 (1992)). Hence, the interactionbetween p53 and HDM2 represents a key potential therapeutic target. Onemechanism by which MDM2 can promote tumorogenesis is by its inhibitoryaction on p53. The tumor suppressor functions of p53 control a pivotalcheckpoint in the control of cell cycling (reviewed in Levine, A. J.,Cell 88:323-331 (1997)). p53 is a transcription factor for a number ofproteins that cause cell cycle arrest or cell death by apoptosis. Thelevel and transcriptional activity of p53 are increased by damage tocellular DNA. The MDM2 protein inhibits p53 function by binding to anamphipathic N-terminal helix of p53, abrogating the interaction of p53with other proteins and its transactivation activity. The interactionwith MDM2 also targets p53 for ubiquitin dependent protein degradation.MDM2 exhibits p53 independent effects on cell cycling as well, possiblyby direct interaction with some of the downstream effectors such as pRBand EF2 (Reviewed in Zhang, R. and Wang, H., Cur. Pharm. Des. 6:393-416(2000)).

Blocking HDM2 from binding p53 would be therapeutically useful inrestoring cell cycle control to cells that overexpress HDM2 as a frontline cancer treatment. More generally, inhibition of HDM2 may increasethe effectiveness of chemotherapy and radiation in p53 normal cancers byenhancing apoptosis and growth arrest signaling pathways.

A need continues to exist for potent, small molecules that inhibit theinteractions between HDM2 and p53.

SUMMARY OF THE INVENTION

A first aspect of the present invention is directed to novel compoundsof Formula I.

A second aspect of the present invention is directed to pharmaceuticalcompositions comprising at least one compound of Formula I, or a saltthereof, and one or more pharmaceutically acceptable excipients.

A third aspect of the present invention is directed to a method ofinhibiting the binding of a protein encoded by hdm2 to p53 protein,comprising contacting p53 or one or more proteins encoded by mdm2, withone or more compounds of Formula I.

A fourth aspect of the invention is directed to a method of inducingapoptosis, comprising contacting an animal with a composition comprisinga pharmaceutically effective amount of at least one compound of FormulaI, or a salt thereof, and one or more pharmaceutically-acceptableexcipients.

A fifth aspect of the present invention is directed to a method oftreating cancer. The method comprises contacting an animal with (a) apharmaceutically effective amount of an antineoplastic agent and (b) apharmaceutically effective amount of at least one compound of Formula I,or a salt thereof, and one or more pharmaceutically-acceptableexcipients.

A sixth aspect of the present invention is directed to a method oftreating cancer, comprising contacting an animal with a compositioncomprising (a) a pharmaceutically effective amount of at least onecompound of Formula I, or a salt thereof, (b) one or more agents thatinduce or cause DNA damage, and (c) one or morepharmaceutically-acceptable excipients.

A seventh aspect of the present invention is directed to a method ofsynthesizing compounds of Formula I.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A novel class of small molecules that bind to HDM2 and/or MDM2 has nowbeen discovered. By interfering with HDM2-p53 or MDM2-p53 interactions,these compounds increase the intracellular concentration of p53. Thesesmall molecules, therefore, have therapeutic utility in sensitizingtumor cells for chemotherapy. In tumor types particularly sensitive toan increase in functional p53, compounds of this type will be sufficientto induce apoptosis. Compounds of the present invention are also usefulin treating tumor types in which HDM2 or MDM2 is overexpressed.

Compounds of the present invention include compounds of Formula I:

or a solvate, hydrate or pharmaceutically acceptable salt thereof;wherein:

X and Y are independently —C(O)—, —CH₂— or —C(S)—;

R¹, R², R³, and R⁴ are independently hydrogen, halo, alkyl, alkenyl,alkynyl, cycloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheteroaralkyl, alkoxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, cyano, amino, alkanoylamino, nitro, hydroxy,carboxy, or alkoxycarbonyl;

or R¹ and R², or R² and R³, or R³ and R⁴ are taken together to form—(CH₂)_(u)—, where u is 3-6, —CH═CH—H═CH— or —CH₂CH═CHCH₂—;

R⁵ is hydrogen, alkyl, cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aralkyl,optionally substituted heteroaralkyl, carboxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl,alkylaminocarbonyl or alkylaminocarbonylalkyl;

R⁶ is cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl,heteroarylalkyl, or a saturated or partially unsaturated heterocycle,each of which is optionally substituted;

R⁷ and R⁸ are independently hydrogen or alkyl;

R⁹ is cycloalkyl, aryl, heteroaryl, a saturated or partially unsaturatedheterocycle, cycloalkyl(alkyl) aralkyl or heteroarylalkyl, each of whichis optionally substituted; and

R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M, —(CH₂)_(i)—OH or—(CH₂)_(j)—CONR^(c)R^(d) where

R^(b) is hydrogen, alkyl, optionally substituted cycloalkyl, oroptionally substituted, saturated or partially unsaturated heterocycle;

M is a cation;

R^(c) and R^(d) are independently hydrogen, alkyl, hydroxyalkyl,carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, and an optionallysubstituted, saturated or partially unsaturated heterocycle; and

n is 0-8, m is 0-8, i is 1-8 and j is 0-8.

Preferred compounds include compounds of Formula I, or salts thereof,wherein:

R¹, R², R³, and R⁴ are independently hydrogen, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, optionally substituted C₆₋₁₀aryl, optionally substituted C₆₋₁₀ ar(C₁₋₆)alkyl, optionally substitutedheteroaryl, optionally substituted heteroar(C₁₋₆)alkyl, C₁₋₆ alkoxy,optionally substituted C₆₋₁₀ aryloxy, optionally substitutedheteroaryloxy, cyano, amino, alkanoyl amino, nitro, hydroxy, carboxy, orC₁₋₆ alkoxycarbonyl;

or R¹ and R², or R² and R³, or R³ and R⁴ are taken together to form—CH═CH—CH═CH— or —CH₂CH═CHCH₂—;

R⁵ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, optionally substitutedC₆₋₁₀ aryl, optionally substituted heteroaryl, optionally substitutedC₆₋₁₀ ar(C₁₋₆)alkyl, optionally substituted heteroar(C₁₋₆)alkyl,carboxy(C₁₋₆)alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminocarbonyl, aminocarbonyl(C₁₋₆)alkyl, or C₁₋₆alkylaminocarbonyl(C₁₋₆)alkyl;

R⁶ is C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, heteroaryl, a saturated or partiallyunsaturated heterocycle, C₃₋₇ cycloalkyl(C₁₋₄)alkyl, C₆₋₁₀ ar(C₁₋₆)alkylor heteroaryl(C₁₋₆)alkyl, each of which is optionally ring substitutedby one or more substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl,phenoxy, benzyloxy, 5-10 membered heteroaryl, hydroxy, C₁₋₄ alkoxy, C₁₋₄alkylenedioxy, halo, C₁₋₄ haloalkyl, C₁₋₄ alkylthio, thio, amino,mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, and nitro;

R⁷ is hydrogen or C₁₋₆ alkyl;

R⁸ is hydrogen or C₁₋₆ alkyl,

R⁹ is C₃₋₇ cycloalkyl, a saturated or partially unsaturated heterocycle,C₆₋₁₀ aryl, heteroaryl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, C₆₋₁₀ar(C₁₋₆)alkylor heteroaryl(C₁₋₆)alkyl, each of which is optionally substituted by oneor more substituents independently selected from the group consisting ofC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylenedioxy, carboxy, halo,C₁₋₄ haloalkyl, trifluoromethoxy, C₁₋₄ alkylthio, thio, amino,mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, and nitro; and

R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M, —(CH₂)_(i)—OH or—(CH₂)_(j)—CONR^(c)R^(d), where

-   -   R^(b) is hydrogen, C₁₋₆ alkyl, optionally substituted C₃₋₇        cycloalkyl, or an optionally substituted, saturated or partially        unsaturated heterocycle;    -   M is a cation;    -   R^(c) and R^(d) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆        hydroxyalkyl, C₁₋₆ carboxyalkyl, aminoalkyl, optionally        substituted C₃₋₇ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₆₋₁₀ ar(C₁₋₆)alkyl, optionally        substituted heteroaryl, optionally substituted        heteroaryl(C₁₋₆)alkyl, or an optionally substituted, saturated        or partially unsaturated heterocycle; and

n is 0-4, m is 0-4, i is 1-4 and j is 0-4.

In one preferred embodiment

R¹ and R⁴ are both hydrogen;

R² is hydrogen, halo, C₁₋₆ alkyl, C₁₋₄ hydroxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, acetyl amino, cyano, amino, C₁₋₆ alkoxy,phenyl, thienyl, furanyl, and pyrrolyl, wherein said phenyl, thienyl andfuranyl are optionally substituted by one or more substituentsindependently selected from the group consisting of halo, C₁₋₄ alkoxy,C₁₋₄ alkyl, amino, methylenedioxy, and ethylenedioxy,

R³ is hydrogen, C₁₋₆ alkyl, phenyl, or halo; or R² and R³ are takentogether to form —CH═CH—CH═CH—;

R⁵ is hydrogen; C₁₋₆ alkyl; C₁₋₆ hydroxyalkyl; carboxy(C₁₋₆)alkyl; C₁₋₆alkylcarbamoyl(C₁₋₆)alkyl; C₁₋₆ alkoxycarbonylamino(C₁₋₆)alkyl; C₃₋₇cycloalkyl(C₁₋₆)alkyl; C₆₋₁₀ aryl, optionally substituted by C₁₋₄ alkylor halo; C₆₋₁₀ ar(C₁₋₄)alkyl optionally substituted by C₁₋₄ alkyl orhalo; and pyridyl(C₁₋₄)alkyl;

R⁶ is C₆₋₁₀ aryl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl,pyridyl, quinolinyl, C₃₋₇ cycloalkenyl or cubanyl, each of which isoptionally substituted by one or more substituents independentlyselected from the group consisting of halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₁₋₄ alkoxy, halo(C₁₋₄)alkoxy, trifluoromethyl, trifluoromethoxy, C₁₋₄alkylsulfanyl, trifluoromethylsulfanyl, cyano, thienyl, phenyl,halophenyl, trifluoromethylphenyl, phenoxy, benzyloxy and pyrrolidinyl;

R⁷ is hydrogen or C₁₋₆ alkyl;

R⁸ is hydrogen or C₁₋₆ alkyl;

R⁹ is C₃₋₇ cycloalkyl, C₆₋₁₀ aryl, heteroaryl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl or heteroaryl(C₁₋₆)alkyl,each of which is optionally substituted on the ring portion; and

R¹⁰ is —CH₂)_(n)—CO₂R^(b) or —(CH₂)_(m)—CO₂M, where R^(b) is hydrogen,C₁₋₆ alkyl, optionally substituted C₃₋₇ cycloalkyl, or optionallysubstituted heterocycloalkyl, M is a cation n and m are independently 0,1, 2, 3 or 4; or

R¹⁰ is-(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d), where

R^(c) and R^(d) are independently hydrogen, hydroxy, C₃₋₇ cycloalkyl,

-   -   -   C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ carboxyalkyl, C₁₋₆            aminoalkyl, optionally substituted, phenyl,-or optionally            substituted benzyl; and        -   i is 1, 2, 3, or 4, and j is 0, 1, 2, 3 or 4.

Preferred compounds include those wherein R¹ is hydrogen.

Preferred compounds include those wherein R⁴ is hydrogen.

Useful values of R² include hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl,halophenyl, hydroxyphenyl, C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl,aminophenyl, C₁₋₆ alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl,C₁₋₆ alkylthienyl, furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl andcyano.

Useful values of R² also include hydrogen, iodo, fluoro, chloro, bromo,methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl, cyclopropyl,ethynyl, acetylamino, methoxy, phenyl, 3-chlorophenyl, 4-chlorophenyl,4-hydroxyphenyl, 3-methoxyphenyl, 4-methylphenyl, 3-methylphenyl,3-isopropylphenyl, 3-aminophenyl, 3,4-methylenedioxyphenyl,4-hydroxycarbonylphenyl, thien-3-yl, 4-methylthien-2-yl, furan-2-yl,1H-pyrrol-3-yl, amino, 2-hydroxyethyl, hydroxymethyl, furan-3-yl, vinyland cyano.

Preferred compounds include those wherein R² is halo or phenyl. Morepreferred compounds include those wherein R² is iodo.

Useful values of R³ include hydrogen, phenyl, fluoro, chloro, iodo andmethyl. Preferred compounds are those wherein R³ is hydrogen.

Useful values of R⁵ include hydrogen, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl,carboxy(C₁₋₆)alkyl, C₁₋₆ alkylphenyl, C₁₋₆ alkylbenzyl, phenethyl,phenyl(C₁₋₆)alkyl, naphthyl(C₁₋₆)alkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl,pyridyl(C₁₋₆)alkyl, C₁₋₆ alkoxycarbonylamino(C₁₋₆)alkyl, and C₁₋₆alkylcarbamoyl(C₁₋₆)alkyl.

Useful values of R⁵ also include hydrogen, methyl, carboxymethyl,3-methylbutyl, 2-methylpropyl, isopropyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, phenyl, benzyl, phenethyl,3-phenylpropyl, naphthalen-2-ylmethyl, cyclohexylmethyl,cyclopentylmethyl, cyclobutylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl,pyridylmethyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,2-carboxyethyl, 2-t-butoxycarbonylaminoethyl, 2-pyrid-2-ylethyl,methylcarbamoylmethyl and 2,3-dihydroxypropyl.

Preferred compounds include those wherein R⁵ is hydrogen.

Useful values of R⁶ include optionally substituted C₆₋₁₀ aryl.

Useful values of R⁶ also include trifluoromethylphenyl, halophenyl, C₁₋₆alkylphenyl, C₁₋₆ alkoxyphenyl, halo(C₁₋₄)alkoxyphenyl, naphthyl,benzyloxyphenyl, phenoxyphenyl, dihydrobenzodioxinyl,trifluoromethylhalophenyl, pyridyl, thienyl, C₁₋₆ alkylthienyl,halothienyl, bithienyl, C₁₋₆ alkylbenzothienyl, (halophenyl)furanyl,quinolinyl, biphenyl, indolyl, (trifluoromethylsulfanyl)phenyl,(trifluoromethylphenyl)furanyl, halo(C₁₋₄)alkoxyphenyl, benzofuranyl,cyanophenyl, halopyridyl, (methylsulfanyl)phenyl, pyrrolidinylphenyl,C₂₋₆ alkenyl(C₃₋₇)cycloalkenyl, cubanyl and halocubanyl.

Useful values of R⁶ also include 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl,3chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-ethylphenyl,4-trifluoromethoxyphenyl, 4-isopropylphenyl, phenyl, 4-methoxy-phenyl,naphthalen-2-yl, 4-tert-butylphenyl, 4-benzyloxyphenyl, 4-phenoxyphenyl,3,4-dichlorophenyl, 3,4-dimethoxyphenyl,2,3-dihydrobenzo[1,4]dioxin-6-yl, 4-bromo-2-fluorophenyl,2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl,4-chloro-3-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, pyrid-2-yl,pyrid-3-yl, pyridyl, thien-3-yl, 5-methylthien-2-yl, 3-methylthien-2-yl,4-bromothien-2-yl, 5-[2,2′]bithienyl, 3-methylbenzo[b]thiophen-2-yl,5-(2-chlorophenyl)-furan-2-yl, 5-(3-chlorophenyl)-furan-2-yl,quinolin-3-yl, biphen-4-yl, indol-2-yl, indol-3-yl,4-trifluoromethylsulfanylphenyl, 5-(3-trifluoromethylphenyl)furan-2-yl,4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-difluoromethoxyphenyl,benzofuran-2-yl, 4-cyanophenyl, 6-chloropyrid-3-yl,4-methylsulfanylphenyl, 4-pyrrolidin-1-ylphenyl, 5-chlorothien-2-yl,4-isopropenylcyclohex-1-enyl and 1-chlorocuban-4-yl.

Preferred compounds include those wherein R⁶ is 4-chlorophenyl,4-bromophenyl, 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl. Morepreferred compounds include those wherein R⁶ is 4-chlorophenyl.

Useful values of R⁷ include hydrogen and methyl. Preferred compoundsinclude those wherein R⁷ is hydrogen.

Useful values of R⁸ include hydrogen and methyl. Preferred compoundsinclude those wherein R⁸ is hydrogen.

Useful values of R⁹ include optionally substituted C₆₋₁₀ aryl andoptionally substituted C₆₋₁₀ ar(C₁₋₆)alkyl.

Useful values of R⁹ also include phenyl, 4-chlorophenyl, 4-chlorobenzyl,benzyl, cyclohexyl, cyclohexylmethyl, 4-hydroxyphenyl, pyridylmethyl,4-fluorophenyl, 4-trifluoromethylphenyl, 4-iodobenzyl, 4-bromobenzyl,thien-2-yl, thien-2-ylmethyl, naphth-2-ylmethyl, pyrid-2-ylethyl,3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-chloro-3-fluorophenyl,2-fluoro-4-trifluoromethylphenyl, 4-hydroxycarbonylphenyl,naphthalen-2-yl, naphthalen-1-yl, 4-iodophenyl, 4-bromophenyl,3,4-dichlorophenyl, 2-chlorophenyl, 4-tert-butylphenyl,4-isopropylphenyl, 3-chlorophenyl, 4-trifluoromethoxyphenyl, and3-hydroxyphenyl, 4-hydroxybenzyl, 4-trifluoromethylbenzyl,naphth-1-ylmethyl, 6-chloropyrid-3-yl and 6-methylpyrid-3-yl.

Preferred compounds include those wherein R⁹ is halophenyl orhalobenzyl. More preferred compounds include those wherein R⁹ is phenylor 4-chlorophenyl.

Useful values of R¹⁰ include —COOR^(b) and —CH₂—COOR^(b), where R^(b) ishydrogen or C₁₋₆ alkyl; and —COOM and —CH₂COOM, where M is Na⁺ or K⁺.

Preferred compounds include those wherein R¹⁰ is —COOR^(b) or—CH₂—COOR^(b), where R^(b) is hydrogen, methyl, ethyl, propyl ortert-butyl.

Preferred compounds also include those wherein R¹⁰ is —COOH or —COOM,where M is Na¹⁰ or K⁺.

Useful values of R¹⁰ also include —CH₂OH and —CH₂CH₂OH; and—CH₂—CONR^(c)R^(d) and —CONR^(c)R^(d), where R^(c) and R^(d) areindependently hydrogen, methyl, ethyl, propyl, t-butyl, hydroxymethyl,hydroxyethyl, hydroxypropyl, aminomethyl, aminoethyl, aminopropyl,carboxymethyl, carboxyethyl, carboxypropyl, cyclopentyl, cyclohexyl,phenyl or benzyl.

Preferred compounds include those wherein R¹⁰ is —CH₂—CONR^(c)R^(d) or—CONR^(c)R^(d), where R^(c) and R^(d) are independently hydrogen,methyl, hydroxyethyl, 3-carboxypropyl, 1-carboxy-2-methylpropyl,hydroxy, 4-carboxybutyl, 5-carboxypentyl, 2-(methoxycarbonyl)ethyl or2-(hydroxyguanidino)ethyl.

In each of the above embodiments, X and Y are independently —C(O)—,—CH₂— or —C(S)—, more preferably —C(O)— or —C(S)—, most preferably—C(O)—.

A second aspect of the present invention is directed to pharmaceuticalcompositions comprising

a) at least one compound of Formula I or a pharmaceutically acceptablesalt thereof; and

b) one or more pharmaceutically-acceptable excipients.

Preferably, the pharmaceutical composition is sterile.

A third aspect of the present invention is directed to a method ofinhibiting the binding of a protein encoded by mdm2 to p53 protein,comprising contacting p53 or one or more proteins encoded by mdm2 withone or more compounds of Formula I, wherein R¹—R¹⁰ are defined as above.

A fourth aspect of the invention is directed to a method of inducingapoptosis, comprising contacting an animal with a composition comprisinga pharmaceutically effective amount of at least one compound of FormulaI, or a salt thereof, wherein R¹—R¹⁰ are defined as above, andoptionally one or more pharmaceutically-acceptable excipients.

A fifth aspect of the present invention is directed to a method oftreating cancer, comprising contacting an animal with (a) apharmaceutically effective amount of an antineoplastic agent, and (b) apharmaceutically effective amount of at least one compound of Formula I,or a salt thereof, wherein R¹-R¹⁰, are defined as above, and optionallyone or more pharmaceutically-acceptable excipients, in combination with(a), (b), or (a) and (b).

A sixth aspect of the present invention is directed to a method oftreating cancer, comprising contacting an animal with a compositioncomprising (a) a pharmaceutically effective amount of at least onecompound of Formula I, or a salt thereof, (b) one or more agents thatinduce or cause DNA damage, and optionally (c) one or morepharmaceutically-acceptable excipients.

A seventh aspect of the present invention is directed to a method ofmaking compounds of Formula I.

Compounds within the scope of the invention are described in theExamples. Examples of preferred compounds include:

(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

2-[7-bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-(4-chloro-phenyl)-propionicacid;

2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4-diazepin-4-yl]-acetamide;

[7-chloro-3-(4-chloro-phenyl)-2-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid;

(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethynyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-p-tolyl-aceticacid;

(4-chloro-3-fluorophenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

(4-chloro-phenyl)-[3-(4-chlorophenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

(4-bromo-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

[3-(4-chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid;

[3-(4-chlorophenyl)-7-phenyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenylaceticacid;

[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-fluoro-phenyl)-aceticacid;

[3-(4-chloro-phenyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-trifluoromethyl-phenyl)-aceticacid;

(4-chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-aceticacid;

(4-chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-aceticacid;

[3-(4-bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid;

[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-isopropyl-phenyl)-aceticacid;

(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-cyano-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid;

3-(4-chloro-phenyl)-4-(3-hydroxy-1-phenyl-propyl)-7-iodo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione;

2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-hydroxy-acetamide;

[7-bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid;

[8-chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid;

5-{2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-pentanoicacid;

3-{2-(4-chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino)-propionicacid;

5-[4-[carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl]-pentanoicacid;

and pharmaceutically acceptable salts thereof.

Additional examples of preferred compounds include:

(4-chlorophenyl)-[3-(4-chlorophenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]aceticacid,

3-(4-chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid;

(4-chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-5-oxo-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid,

3-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one;

3-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one;

and pharmaceutically-acceptable salts thereof.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabeled compound of the invention, administering it parenterally ina detectable dose to an animal such as rat, mouse, guinea pig, monkey,or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms. The present invention is also meant toencompass all such possible forms as well as their racemic and resolvedforms and mixtures thereof. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended to include both E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached, or a sulfur atom to which three different groupsare attached, where the sulfur atom and its attached groups form asulfoxide, sulfinic ester, sulfonium salt or sulfite.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposable on its mirror image and hence optically active whereinthe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule. The phrase“enantomeric excess” refers to a mixture wherein one enantiomer ispresent is a greater concentration than its mirror image molecule.

The compounds of Formula I may also be solvated, especially hydrated.Hydration may occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration may occur overtime due to the hygroscopic nature of the compounds.

Certain compounds within the scope of Formula I are derivatives referredto as “prodrugs.” The expression “prodrug” denotes a derivative of aknown direct acting drug, which derivative has enhanced deliverycharacteristics and therapeutic value as compared to the drug, and istransformed into the active drug by an enzymatic or chemical process.Prodrugs are derivatives of the compounds of the invention which havemetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention which arepharmaceutically active in vivo. For example, ester derivatives ofcompounds of this invention are often active in vivo, but not in vitro.Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid derivative formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H, Design of Prodrugs,pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound withan amine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Usefulprodrugs are those where R^(b) is alkyl, alkenyl, alkynyl, or arylalkyl.

When any variable occurs more than one time in any constituent or inFormula I, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

DEFINITIONS

The term “alkyl” as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to 10carbons, unless the chain length is otherwise limited, such as methyl,ethyl, propyl, isopropyl, butyl, i-butyl, isobutyl, pentyl, hexyl,isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,nonyl, or decyl.

The term “alkenyl” is used herein to mean a straight or branched chainradical of 2-10 carbon atoms, unless the chain length is otherwiselimited, wherein there is at least one double bond between two of thecarbon atoms in the chain, including, but not limited to, ethenyl,1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, andthe like. Preferably, the alkenyl chain is 2 to 8 carbon atoms inlength, most preferably from 2 to 4 carbon atoms in length.

The term “alkynyl” is used herein to mean a straight or branched chainradical of 2-10 carbon atoms, unless the chain length is otherwiselimited, wherein there is at least one triple bond between two of thecarbon atoms in the chain, including, but not limited to, ethynyl,1-propynyl, 2-propynyl, and the like. Preferably, the alkynyl chain is 2to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms inlength.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinyl or ethenyllinkage, is preferably not directly attached to a nitrogen, oxygen orsulfur moiety.

The term “alkoxy” or “alkyloxy” refers to any of the above alkyl groupslinked to an oxygen atom. Typical examples are methoxy, ethoxy,isopropyloxy, sec-butyloxy, and t-butyloxy.

The term “aryl” as employed herein by itself or as part of another grouprefers to monocyclic or bicyclic aromatic groups containing from 6 to 12carbons in the ring portion, preferably 6-10 carbons in the ringportion. Typical examples include phenyl, biphenyl, naphthyl ortetrahydronaphthyl.

The term “aralkyl” or “arylalkyl” as employed herein by itself or aspart of another group refers to C₁₋₆ alkyl groups as discussed abovehaving an aryl substituent, such as benzyl, phenylethyl or2-naphthylmethyl.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14 pi electrons shared in a cyclic array, andcontaining carbon atoms and 1, 2, 3, or 4 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, and tetrazolyl groups).

The phrase “saturated or partially unsaturated heterocycle” as employedherein, by itself or as part of another group, refers to a saturated orpartially unsaturated ring system having 5 to 14 ring atoms selectedfrom carbon atoms and 1, 2, 3, or 4 oxygen, nitrogen, or sulfurheteroatoms. Typical saturated examples include pyrrolidinyl,imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl,piperidyl, piperazinyl, quinuclidinyl, morpholinyl, and dioxacyclohexyl.Typical partially unsaturated examples include pyrrolinyl, imidazolinyl,pyrazolinyl, dihydropyridinyl, tetrahydropyridinyl, and dihydropyranyl.Either of these systems can be optionally fused to a benzene ring.

The terms “heteroarylalkyl” or “heteroaralkyl” as employed herein bothrefer to a heteroaryl group attached to an alkyl group. Typical examplesinclude 2-(3-pyridyl)ethyl, 3-(2-furyl)-n-propyl,3-(3-thienyl)-n-propyl, and 4-(1-isoquinolinyl)-n-butyl.

The term “cycloalkyl” as employed herein by itself or as part of anothergroup refers to cycloalkyl groups containing 3 to 9 carbon atoms.Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl.

The term “cycloalkylalkyl” or “cycloalkyl(alkyl)” as employed herein, byitself or as part of another group, refers to a cycloalkyl groupattached to an alkyl group. Typical examples are 2-cyclopentylethyl,cyclohexylmethyl, cyclopentylmethyl, 3-cyclohexyl-n-propyl, and5-cyclobutyl-n-pentyl.

The term “cycloalkenyl” as employed herein, by itself or as part ofanother group, refers to cycloalkenyl groups containing 3 to 9 carbonatoms and 1 to 3 carbon-carbon double bonds. Typical examples includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl,cyclooctadienyl, cyclooctatrienyl, cyclononenyl, and cyclononadienyl.

The term “halogen” or “halo” as employed herein by itself or as part ofanother group refers to chlorine, bromine, fluorine or iodine.

The term “monoalkylamine” or “monoalkylamino” as employed herein byitself or as part of another group refers to the group NH₂ wherein onehydrogen has been replaced by an alkyl group, as defined above.

The term “dialkylamine” or “dialkylamino” as employed herein by itselfor as part of another group refers to the group NH₂ wherein bothhydrogens have been replaced by alkyl groups, as defined above.

The term “hydroxyalkyl” as employed herein refers to any of the abovealkyl groups wherein one or more hydrogens thereof are substituted byone or more hydroxyl moieties.

The term “haloalkyl” as employed herein refers to any of the above alkylgroups wherein one or more hydrogens thereof are substituted by one ormore halo moieties. Typical examples include fluoromethyl,difluoromethyl, trifluoromethyl, trichloroethyl, trifluoroethyl,fluoropropyl, and bromobutyl.

The term “carboxyalkyl” as employed herein refers to any of the abovealkyl groups wherein one or more hydrogens thereof are substituted byone or more carboxylic acid moieties.

The term “heteroatom” is used herein to mean an oxygen atom (“O”), asulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized thatwhen the heteroatom is nitrogen, it may form an NR^(a)R^(b) moiety,wherein R^(a) and R^(b) are, independently from one another, hydrogen orC₁ to C₈ alkyl, or together with the nitrogen to which they are boundform a saturated or unsaturated 5-, 6-, or 7-membered ring.

The phrase “optionally substituted” when not explicitly defined refersto a group or groups being optionally substituted with one or moresubstituents independently selected from the group consisting ofhydroxy, nitro, trifluoromethyl, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylenedioxy, C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₆₋₁₀ aryl, phenoxy, benzyloxy, 5-10membered heteroaryl; C₁₋₆ aminoalkoxy, amino, mono(C₁₋₄)alkylamino,di(C₁₋₄)alkylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino,C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonylalkyl, carboxy, C₂₋₆hydroxyalkoxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy,mono(C₁₋₄)alkylamino(C₂₋₆)alkoxy, di(C₁₋₄)alkylamino(C₂₋₆)alkoxy C₂₋₁₀mono(carboxyalkyl)amino, bis(C₂₋₁₀ carboxyalkyl)amino, C₂₋₆carboxyalkoxy, C₂₋₆ carboxyalkyl, carboxyalkylamino, guanidinoalkyl,hydroxyguanidinoalkyl, cyano, trifluoromethoxy, or perfluoroethoxy.

Preferred optional substituents include one or more substituentsindependently selected from the group consisting of nitro, hydroxy,carboxy, C₁₋₄ alkoxy, C₁₋₄ alkyl, halo, C₁₋₄ haloalkyl, C₁₋₄ alkylthio,thio, amino, mono(C₁₋₄)alkylamino, and di(C₁₋₄)alkylamino.

“mdm2” is used herein to mean the murine double minute 2 gene, andhomologous genes found in other animals.

“MDM2” is used herein to mean a protein obtained as a result ofexpression of the mdm2 oncogene. Within the meaning of this term, itwill be understood that MDM2 encompasses all proteins encoded by mdm2,mutants thereof, alternative splice proteins thereof, and phosphorylatedproteins thereof. Additionally, as used herein, it will be understoodthat the term “MDM2” includes MDM2 homologues of other animals (e.g.,HDM2).

“hdm2” is used herein to mean the human gene which is homologous to themouse mdm2.

“HDM2” is used herein to mean a protein obtained as a result ofexpression of the hdm2 oncogene. Within the meaning of this term, itwill be understood that HDM2 encompasses all proteins encoded by thehdm2, mutants thereof, alternative splice proteins thereof, andphosphorylated proteins thereof.

The phrase “antineoplastic agent” is used herein to mean any agent thatis used to treat or prevent cancer or other conditions comprisinguncontrolled proliferation and growth of cells. Antineoplastic agentsinclude anticancer agents.

The phrase “contacting one or more proteins” is used herein to meanplacing a compound of the present invention in a solution with one ormore proteins of interest. A compound of Formula I and one or moreproteins of interest may be in solution together in an aqueous solution,non-aqueous solution, or combination of an aqueous solution andnon-aqueous solution. Other proteins may be present in solution alongwith the compound of Formula I and the protein of interest. Otherinorganic or organic molecules may be present in the solution. Suchinorganic and organic molecules include, but are not limited to, NaCl,HEPES, and octyl glucoside. The solution may be within an animal cell oroutside of an animal cell.

The phrase “inhibiting the binding” is used herein to mean preventing orreducing the direct or indirect association of one or more molecules,peptides, proteins, enzymes, or receptors; or preventing or reducing thenormal activity of one or more molecules, peptides, proteins, enzymes,or receptors.

The phrase “inducing apoptosis” is used herein to mean causing directlyor indirectly a cell of animal origin to undergo apoptosis, a process ofcontrolled, or programmed, cellular death.

The phrase “HDM2 inhibitor” is used herein to describe an agent whichinhibits the function of HDM2 in the assay described in Example 217.

The pharmaceutically-acceptable salts of the compounds of Formula I (inthe form of water- or oil-soluble or dispersible products) include theconventional non-toxic salts or the quaternary ammonium salts which areformed, e.g., from inorganic or organic acids or bases. Examples of suchacid addition salts include acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; and aralkyl halides likebenzyl and phenethyl bromides and others. Preferred acids for formingacid addition salts include HCl, acetic acid, trifluoroacetic acid andfumaric acid.

Compositions and Methods of Use

Compositions of the present invention include pharmaceuticalcompositions comprising a compound of Formula I, wherein R¹-R¹⁰ aredefined above, and one or more pharmaceutically acceptable excipients.Preferred compositions of the present invention are pharmaceuticalcompositions comprising a compound selected from a preferred group ofcompounds of Formula I as defined above, and one or morepharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention can be administered toany animal that can experience the beneficial effects of the compoundsof the invention. Foremost among such animals are humans, although theinvention is not intended to be so limited.

The pharmaceutical compositions of the present invention can beadministered by any means that achieve their intended purpose. Forexample, administration can be by subcutaneous, intravenous,intramuscular, intraperitoneal, buccal, or ocular routes, rectally,parenterally, intrasystemically, intravaginally, topically (as bypowders, ointments, drops or transdermal patch), or as an oral or nasalspray. Alternatively, or concurrently, administration can be by the oralroute. The dosage administered will be dependent upon the age, health,and weight of the recipient, kind of concurrent treatment, if any,frequency of treatment, and the nature of the effect desired.

In addition to the pharmacologically active compounds, the newpharmaceutical preparations can contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active compounds into preparations that canbe used pharmaceutically.

The pharmaceutical preparations of the present invention aremanufactured in a manner that is, itself, known, for example, by meansof conventional mixing, granulating, dragée-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragée cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample, lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders, such as,starch paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as, the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as, sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as, magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragée cores are provided withsuitable coatings that, if desired, are resistant to gastric juices. Forthis purpose, concentrated saccharide solutions can be used, which cancontain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol,and/or titanium dioxide, lacquer solutions and suitable organic solventsor solvent mixtures. In order to produce coatings resistant to gastricjuices, solutions of suitable cellulose preparations, such as,acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate,are used. Dye stuffs or pigments can be added to the tablets or dragéecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as, glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules that may be mixed with fillers such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as, fattyoils or liquid paraffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts, alkaline solutions and cyclodextrin inclusioncomplexes. Especially preferred alkaline salts are ammonium saltsprepared, for example, with Tris, choline hydroxide, Bis-Tris propane,N-methylglucamine, or arginine. One or more modified or unmodifiedcyclodextrins can be employed to stabilize and increase the watersolubility of compounds of the present invention. Useful cyclodextrinsfor this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604,and 5,024,998.

In addition, suspensions of the active compounds as appropriate oilyinjection suspensions can be administered. Suitable lipophilic solventsor vehicles include fatty oils, for example, sesame oil, or syntheticfatty acid esters, for example, ethyl oleate or triglycerides orpolyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueousinjection suspensions can contain substances that increase the viscosityof the suspension, for example, sodium carboxymethyl cellulose,sorbitol, and/or dextran. Optionally, the suspension may also containstabilizers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols, and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Topical administration includes administration to the skin or mucosa,including surfaces of the lung and eye. Compositions for topicaladministration, including those for inhalation, may be prepared as a drypowder which may be pressurized or non-pressurized. In nonpressurizedpowder compositions, the active ingredients in finely divided form maybe used in admixture with a larger-sized pharmaceutically acceptableinert carrier comprising particles having a size, for example, of up to100 micrometers in diameter. Suitable inert carriers include sugars suchas lactose. Desirably, at least 95% by weight of the particles of theactive ingredient have an effective particle size in the range of 0.01to 10 micrometers.

Alternatively, the composition may be pressurized and contain acompressed gas, such as nitrogen or a liquefied gas propellant. Theliquefied propellant medium and indeed the total composition arepreferably such that the active ingredients do not dissolve therein toany substantial extent. The pressurized composition may also contain asurface-active agent. The surface-active agent may be a liquid or solidnon-ionic surface-active agent or may be a solid anionic surface-activeagent It is preferred to use the solid anionic surface-active agent inthe form of a sodium salt.

A further form of topical administration is to the eye. The compoundsand compositions of the present invention are delivered in apharmaceutically acceptable ophthalmic vehicle, such that the compoundsare maintained in contact with the ocular surface for a sufficient timeperiod to allow the compounds to penetrate the corneal and internalregions of the eye, as for example the anterior chamber, posteriorchamber, vitreous body, aqueous humor, vitreous humor, cornea,iris/ciliary, lens, choroid/retina and sclera. The pharmaceuticallyacceptable ophthalmic vehicle may, for example, be an ointment,vegetable oil or an encapsulating material.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable non-irritating excipients or carrierssuch as cocoa butter, polyethylene glycol or a suppository wax which aresolid at room temperature but liquid at body temperature and thereforemelt in the rectum or vaginal cavity and release the drugs.

The compositions of the present invention can also be administered inthe form of liposomes. As is known in the art, liposomes arm generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto the compounds of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art (see, for example,Prescott, Ed., Meth Cell Biol. 14:33 (1976)).

Compounds of the present invention may be used alone or in combinationwith one or more additional antineoplastic agents. When a compound ofthe present invention is used along with one or more additionalantineoplastic agents, the compound of the present invention may beformulated with the other antineoplastic agent or agents so that apharmaceutical composition comprising a compound of Formula I and one ormore additional antineoplastic agents is administered to an animal.Alternatively, the compound of Formula I can be administered as aseparate pharmaceutical composition from the composition comprising theone or more additional antineoplastic agents. Antineoplastic agents thatmay be used in combination with the compounds of the present inventioninclude compounds selected from the following compounds and classes ofantineoplastic agents:

1. fluoropyrimidines, such as 5-FU (5-fluorouracil), Fluorodeoxyuridine,Ftorafur, 5′-deoxyfluorouridine, UFT, and S-1 Capecitabine;

2. pyrimidine nucleosides, such as Deoxycytidine, Cytosine Arabinoside,Cytarabine, Azacitidine, 5-Azacytosine, Gencitabine, and5-Azacytosine-Arabinoside;

3. purines, such as 6-Mercaptopurine, Thioguanine, Azathioprine,Allopurinol, Cladribine, Fludarabine, Pentostatin, and2-Chloroadenosine;

4. platinum analogues, such as Cisplatin, Carboplatin, Oxaliplatin,Tetraplatin, Platinum-DACH, Ormaplatin, and CI-973, JM-216;

5. anthracyclines/anthracenediones, such as Doxorubicin, Daunorubicin,Epirubicin, Idarubicin, and Mitoxantrone;

6. epipodophyllotoxins, such as Etoposide, and Teniposide;

7. camptothecins, such as Irinotecan, Topotecan, 9-Amino Camptothecin,10,11-Methylenedioxy Camptothecin, 9-Nitro Camptothecin, and TAS 103;

8. hormones and hormonal analogues, such as diethylstilbestrol,Tamoxifen, Toremefine, Tolmudex, Thymitaq, flutamide, fluoxymesterone,bicalutamide, Finasteride, estradiol, Trioxifene, dexamethasone,leuproelin acetate, estramustine, Droloxifene, medroxyprogesterone,megesterol acetate, aminoglutethimide, testolactone, testosterone,diethylstilbestrol, and hydroxyprogesterone;

9. enzymes, proteins and antibodies, such as Asparaginase, Interleukins,Interferons, Leuprolide, and Pegaspargase;

10. vinca alkaloids, such as Vincristine, Vinblastine, Vinorelbine, andVindesine;

11. taxanes, such as Paclitaxel, Taxotere and Docetaxel.

Antineoplastic agents that may be used in combination with compounds ofthe invention also include compounds selected from the followingMechanism-Based Classes:

1. Antihormonals—See classification for Hormones and Hormonal Analogsabove, Anastrozole, Goserelin, and Aminoglutethimide;

2. Antifolates, such as methotrexate, leucovorin, aminopterin,trimetrexate, Trimethoprim, pyritrexim, pyrimethamine, Edatrexate, andMDAM;

3. Antimicrotubule Agents, such as Taxanes, Vinca Alkaloids, andVinorelbine;

4. Alkylating Agents (Classical and Non-Classical), such as NitrogenMustards (Mechlorethamine, Chlorambucil, Melphalan, Uracil Mustard),Oxazaphosphorines (Ifosfamide, Cyclophosphamide, Perfosfamide,Trophosphamide), Alkylsulfonates (Busulfan), Nitrosoureas (Carmustine,Lomustine, Streptozocin), Thiotepa, and Dacarbazine;

5. Antimetabolites, such as Purines, pyrimidines and nucleoside analogs,listed above;

6. Antibiotics, such as Anthracyclines/Anthracenediones, Bleomycin,Dactinomycin, Mitomycin, Plicamycin, Pentostatin, and Streptozocin;

7. Topoisomerase Inhibitors, such as Camptothecins (Topo I),Epipodophyllotoxins, AMSA, VP-16 and Ellipticines (Topo II);

8. Antivirals, such as AZT, acyclovir, penciclovir, famcyclovir,didehydrodideoxythymidine, dideoxycytidine, -SddC, ganciclovir,dideoxyinosine, and viral-specific protease inhibitors;

9. Miscellaneous Cytotoxic Agents, such as Hydroxyurea, Mitotane, FusionToxins, PZA, Bryostatin, Retinoids, Butyric Acid and derivatives,Pentosan, Fumagillin, Mitoxantrone, Bone Marrow Growth Factors, andProcarbazine.

Compounds of the present invention are useful for the treatment ofuncontrolled proliferation of cells and/or cancer. The compounds of thepresent invention may produce beneficial cytostatic and/or cytotoxiceffects. The cytostatic effects include the inhibition of further cellgrowth and/or cell division. The cytotoxic effects include the inductionof cell death by mechanisms that include apoptosis and cellularnecrosis. Specifically, the compounds of the present invention areuseful in treating the following cancers: breast cancer, ovarian cancer,cervical carcinoma, endometrial carcinoma, choriocarcinoma, soft tissuesarcomas, osteosarcomas, rhabdomyosarcomas, leiomyomas, leiomyosarcomas,head and neck cancers, lung and bronchogenic carcinomas, brain tumors,neuroblastomas, esophogeal cancer, colorectal adenocarcinomas, bladdercancer, urothelial cancers, leukemia, lymphoma, malignant melanomas,oral squamous carcinoma, hepatoblastoma, glioblastoma, astrocytoma,medulloblastoina; Ewing's sarcoma, lipoma, liposarcoma, malignantfibroblast histoma, malignant Schwannoma, testicular cancers, thyroidcancers, Wilms' tumor, pancreatic cancers, colorectal adenocarcinoma,tongue carcinoma, gastric carcinoma and nasopharyngeal cancers.Preferably, the present invention is used to treat the cancers selectedfrom the group consisting of breast cancer, choriocarcinoma, soft tissuesarcomas, osteosarcomas, rhabdomyosarcomas, lipoma and liposarcoma. Thecancers and diseases listed above are merely meant to be illustrativeand are by no means meant to be a limiting or exhaustive list.

Additionally, the compounds and compositions described herein are usefulto treat any undesired or detrimental condition that results from theHDM2 protein or the MDM2 protein inhibiting the function of p53 or othercellular proteins that induce apoptosis, induce cellular death, orregulate the cellular cycle.

The compounds of the present invention are also useful at inhibiting theinteraction between p53 and HDMX and/or MDMX. MDMX, also known as MDM4,is a cellular protein involved in the regulation of the cell cycle. Forexample, see Riemenschneider et al., Cancer Res. 59(24):6091-6 (1999).

The compounds of the present invention are also useful for the treatmentand prevention of inflammatory conditions. The compounds of the presentinvention can be administered as anti-inflammatory agents that reducethe degree of or eliminate inflammation of tissues.

The compounds of the present invention are also useful for the treatmentof autoimmune diseases and conditions. The compounds of the presentinvention can be administered to reduce or eliminate the symptoms of anautoimmune disease. Autoimmune diseases include any disease in which ananimal's immune system reacts adversely to a self-antigen. Aself-antigen is any antigen that is normally found in the animal's body.Representative autoimmune diseases include Hashimoto's thyroiditis,Grave's disease, multiple sclerosis, pernicious anemia, Addison'sdisease, insulin-dependent diabetes mellitus, rheumatoid arthritis,systemic lupus erythematosus (SLE or lupus), dermatomyositis, Crohn'sdisease, Wegener's granulomatosis, Anti-Glomerular Basement MembraneDisease, Antiphospholipid Syndrome, Dermatitis Herpetiformis, AllergicEncephalomyelitis, Glomerulonephritis, Membranous Glomerulonephritis,Goodpasture Syndrome, Lambert-Eaton, Myasthenic Syndrome, MyastheniaGravis, Bullous Pemphigoid, Polyendocrinopathies, Reiter's Disease, andStiff-Man Syndrome. Preferably, the present invention is used to treatrheumatoid arthritis or systemic lupus erythematosus.

Inhibitors of the interaction of HDM2 and/or MDM2 and p53 are alsouseful for treating cancer, inhibiting cell growth/replication, andinducing cellular apoptosis and necrosis, when administered along withagents that cause or induce DNA damage (see Chen et al. Proc. Natl. AcadSci. USA 95:195-200 (1998)). Compounds of the present invention may beused to treat cancer, inhibit cell growth/replication, and inducecellular apoptosis and necrosis, by administering a compound of thepresent invention along with agents that cause or induce DNA damage.Agents that induce DNA damage include radiation and chemical agents. Theradiation can be administered either internally or externally. Chemicalagents include any compounds or elements that cause or induce damage toDNA.

The compounds of the present invention may be administered in aneffective amount within the dosage range of about 0.01 mg/kg to about300 mg/kg, preferably between 1.0 mg/kg to 100 mg/kg body weight.Compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

Preparation of Compounds

The present invention is also concerned with the syntheses ofsubstituted 1,4-benzodiazepin-2,5-dione carboxylic acids. The compoundsof the present invention can be prepared utilizing the modification ofUgi condensation products, according to the synthetic pathway shown inScheme 1 or Scheme 2 and as detailed in Keating and Armstrong, J. Am.Chem. Soc., 118: 2574-2583 (1996).

Appropriately substituted or unsubstituted anthranilic acids 1 or 11,amines 3, aldehydes or ketones 2 can be used to prepare the compounds ofthe present invention, wherein R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, and R¹⁰are defined above. The acid compounds of the present invention can beprepared by optional hydrolysis of ester using a base, such as NaOH, inan appropriate solvent, such as methanol/water. In Scheme 2, thestandard Suzuki (Miyaura, N; Yanagi, T.; Suzuki, A., Synth. Commun., 11:513 (1981)) cross coupling condition can be used to introduce R² (fromcompound 12 to 6). While R⁵ is selected as a group other than hydrogen,R⁵ can be introduced by using R⁵Br in the presence of a base, such asNaH, and a solvent; such as THF, or by using a standard Mitsunobucoupling procedure (Mitsunobu, O., Synthesis, 1, (1981)) such as diethylazodicarboxylate, and triphenylphosphine in THF. Compound 7 can beconverted into compound 8 or 9 by using an appropriate reducing reagent,such as BH₃.S(Me)₂, in a solvent such as THF. Compound 10 can be madethrough reaction of compound 7 with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) ina solvent such as THF.

The following examples illustrate, but do not limit, the compounds,methods and compositions of the present invention. Other suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art are within the spirit and scope ofthe invention.

EXAMPLES

The compounds in the examples below were synthesized by the followinggeneral procedures.

General Procedure for the Synthesis of Non-Commercially AvailableAnthranilic Acids

A solution of the appropriate aniline (50.0 mmol) in acetic acid (30.0mL) was heated to 45° C. Bromine (55.5 mmol, 2.8 mL) was then addeddropwise at a rate to keep the temperature between 50-55° C. Thetemperature was held at 50° C. for 1.5 h. The reaction was allowed tocool to ambient temperature and was poured into ice with stirring.Sodium bisulfite (1.0 g) was added and stirred for 30 min. The solutionwas extracted with ethyl acetate (2×50.0 mL). The combined organicextracts were washed with saturated sodium bicarbonate, brine, driedover sodium sulfate, filtered and concentrated in vacuo to give a darkoil. The oil was purified by flash chromatography (silica gel, 5-10%ethyl acetate in hexanes) to give the aryl bromide as a light brown oil.

A solution of the aryl bromide (12.0 mmol) in N,N-dimethylformamide (8.0mL) was stirred at ambient temperature. Copper cyanide (15.0 mmol, 13 g)was added and the reaction was heated to 155° C. for 4 h. The reactionwas allowed to cool and poured into a solution of ethylene diamine (0.1mL) in water (130.0 mL) and stirred for 30 min. The solution wasextracted with ethyl acetate (2×70.0 mL). The organic extracts werecombined and washed with saturated ammonium chloride and brine, driedwith sodium sulfate and concentrated in vacuo. The residue was thenpurified by flash chromatography (silica gel, 10% ethyl acetate inhexane) to give the aryl cyanide as a orange oil.

To a solution of the aryl cyanide (1.5 mmol) in acetic acid (2.0 mL) wasadded 50% sulfuric acid (6.0 mL), The reaction was heated to reflux for2.5 h. The reaction was allowed to cool to ambient temperature andpoured into ice (50.0 g). The solution was neutralized with potassiumhydroxide (6M) and extracted with ethyl acetate (2×40.0 mL). Thecombined organics were washed with brine and dried with sodium sulfate,filtered and dried in vacuo to a solid. The solid was purified by flashchromatography (silica gel, 15% ethyl acetate in methylene chloride to8% methanol in methylene chloride) to give the anthranilic acid as awhite solid.

To a solution of the anthranilic acid (4.2 mmol) in 1,4-dioxane (20.0mL) and 10% sodium hydroxide (5.0 m) was added di-tertbutyl-dicarbonate(12.0 mmol). The reaction was stirred at ambient temperature for 3 days.The reaction was then concentrated in vacuo and poured into water (25.0mL) and ethyl acetate (50.0 mL). It was then acidified with cold 10%citric acid. The organic layers were washed with brine and dried withsodium sulfate and filtered. The organics were concentrated in vacuo toa solid and triturated with hexane. The solids were filtered, and washedwith hexane and dried under high vacuum to give the title compound as awhite solid.

General Procedure for the Synthesis of Benzodiazepine Compounds

A solution of the aldehyde (0.20 mmol) and amino ester (0.20 mmol) inmethanol (2.0 mL) were shaken at ambient temperature for 30 min. To thissolution was added a solution of cyclohexene-1-isontirile (0.21 mmol) inhexanes, followed by the anthranilic acid (0.20 mmol). The solution wasthen shaken for 3 days at ambient temperature. The reaction was cooledin a ice bath and acetyl chloride (0.2 mL) was added slowly. Thesolution was then shaken for an additional 3 h and concentrated invacuo. The residue was purified using pre-packed silica cartridges(methylene chloride to 10% ethyl acetate in methylene chloride). Thepure ester was then concentrated back down in vacuo, dissolved inmethanol (1.5 mL), and 10% sodium hydroxide (0.15 mL) was added. Thereaction mixture was shaken overnight at ambient temperature. Thesolution was then concentrated in vacuo and acidified with hydrochloricacid (1M). The precipitates were extracted with ethyl acetate, separatedand the organics were concentrated in vacuo. The residue was purifiedusing pre-packed silica cartridges (8% ethyl acetate in methylenechloride to 10% methanol in methylene chloride) to give the titlecompounds (0.015-0.050 g).

General Procedure for the Alkylation of Benzodiazepine Compounds

To a solution of the benzodiazepine (0.1 mmol) and alcohol (02 mmol) intetrahydrofuran (1.0 mL) was added triphenylphosphine (0.2 mmol, 0.052g) in tetrahydrofuran (1.0 mL). The solution was shaken 5 minutes thendiisopropyl azodicarboxylate (0.2 mmol, 0.040 mL) was added, and themixture was shaken at ambient temperature overnight. The reaction wasconcentrated in vacuo. The residue was purified by preparative platechromatography (silica gel, 20% ethyl acetate in methylene chloride,bottom band). The isolated ester was dissolved in methanol (1 mL) andsodium hydroxide (1M, 0.2 mL) was added and the reaction mixture wasshaken at ambient temperature overnight. The reaction was concentratedin vacuo, water (0.5 mL) was added, followed by acidification withhydrochloric acid (1M, 0.3 mL). The resulting precipitate was extractedwith ethyl acetate (1 mL) and separated. The organics were dried invacuo and the residues purified using a preparative plate chromatography(silica gel, 8% methanol in methylene chloride, bottom band) to give thetitle compounds (0.012-0.030 g).

General Procedure for the Boronic Acid Cross Coupling of BenzodiazepineCompounds

Benzodiazepine (0.05 mmol), boronic acid (3 eq, 0.15 mmol), andPd(PPh₃)₄ (0.04 eq, 0.002 mmol) were placed in a 2 mL vial equipped witha magnetic stir bar. The vial was fitted with a rubber septum thenevacuated and backflushed with dry N₂. Tetrahydrofuran (THF, 0.8 mL) and2M Na₂CO₃ (0.2 mL) were added to the vial via syringe. The reactionvessel was capped tightly under a N₂ purge then heated to 50° C. for 12h. After cooling to ambient temperature, the solvent was removed underreduced pressure. The residue was then purified by Sep-Pak (10 g silicagel, methylene chloride to 10% ethyl acetate in methylene chloride) togive the title compound.

General Procedure for the Reduction of 1,4-benzodiazepines

1) The benzodiazepine ester (0.070 mmol) was placed in a 4 mL vialequipped with a magnetic stir bar. The vial was fitted with a rubberseptum then evacuated and backflushed with N₂. Borane-dimethylsulfide (4eq., 0.28 mmol, 0.14 mL of 2M THF solution) was added via syringe. Thereaction was stirred at ambient temperature for 15 hours. The solventwas removed under reduced pressure then the residue was dissolved inethyl acetate. The organic phase was washed with 1M NaOH then theaqueous phase was extracted twice with ethyl acetate. The combinedorganic phase was dried over anhydrous magnesium sulfate, filtered, andthe solvent removed under reduced pressure. The mono- and di-reducedproducts were separated by column chromatography on silica gel, elutingwith 10% ethyl acetate in hexanes to give the title compound.

2) The benzodiazepine acid (0.023 mmol) was placed in a 4 mL vialequipped with a magnetic stir bar. The vial was fitted with a rubberseptum then evacuated and backflushed with N₂. Dry THF (1 mL) andborane-dimethylsulfide (4 eq., 0.093 mmol, 46 μL of 2M THF solution)were successively added via syringe and microsyringe, respectively. Thereaction was stirred at ambient temperature for 16 hours then additionalborane-dimethylsulfide (8 eq., 0.186 mmol, 92 μL of 2M THF solution) wasadded to the reaction. The reaction was stirred at ambient temperaturefor an additional 4 hours then the solvent was removed under reducedpressure. The residue was purified by column chromatography using a 5 gsilica gel SEP-pak column, eluting with 20% ethyl acetate indichloromethane. The amide reduction products were further separated bypreparative TLC on a 1000 micron silica gel plate, developed with 20%ethyl acetate in hexanes to give the title compound.

General Procedure for the Preparation of 1,4benzodiazepine Amides

The 1,4-benzodiazepine carboxylic acid (0.057 mmol) and EDC (1.5 eq.,0.086 mmol, 16.5 mg) were placed in a 4 mL vial equipped with a magneticstir bar. The vial was fitted with a rubber septum, then evacuated andbackflushed with dry N₂. Dry dichloromethane (2 mL) was added viasyringe. Once the solids dissolved, the amine (1.5 eq, 0.086 mmol) andtriethylamine (2.5 eq., 0.143 mmol, 20 μL) were successively added viamicrosyringe. The reaction was stirred at ambient temperature for 2hours then the volatiles were removed under reduced pressure. The crudeproduct was purified by column chromatography using a 5 g silica gelSEP-pak column eluting with 50% ethyl acetate in dichloromethane.

Example 1[7-Iodo-2,5-dioxo-3-(4-trifluoromethylphenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 0.4H), 10.52 (s, 0.6H), 7.79 (s,0.4H), 7.72 (s, 0.6H), 7.52-7.22 (m, 9H), 7.00 (m, 1H), 6.63 (d, J=8.4Hz, 0.4H), 6.53 (d, J=8.4 Hz, 0.6H) 6.36 (s, 1H), 5.96 (s, 0.6H), 5.28(s, 0.4H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₆F₃N₂O₄I:580.0;

Found: 580.9(M+H).

Example 2[3-(4-Chlorophenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 0.6H), 10.56 (s, 0.4H), 7.78-6.89(m, 11H), 6.64 (d, J=8.7 Hz, 0.6H), 6.56 (d, J=8.7 Hz, 0.4H), 6.30 (brs, 1H), 5.65 (s, 0.4H), 5.14 (s, 0.6H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₃H₁₆N₂O₄ICl: 546.0; Found: 546.8(M+H).

Example 3[3-(4-ethyl-phenyl)-7-iodo-2,5oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 0.5H), 10.40 (s, 0.5H), 7.78-6.54(m, 12H), 6.35 (s, 0.5H), 6.31 (s, 0.5H), 5.89(s, 0.5H), 5.18 (s, 0.5H).2.38 (m, 2 H), 1.00 (m, 3H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₅H₂₁N₂O₄I: 540.1; Found: 540.8(M+H).

Example 4[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 0.6H), 10.55 (s, 0.4H), 7.69-6.99(m, 11H), 6.63 (d, J=8.6 Hz, 0.6H), 6.55 (d, J=8.6 Hz, 0.4H), 6.31 (brs, 1H), 5.63 (s, 0.4H), 5.18 (s, 0.6H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₄H₁₆F₃N₂O₅I: 596.0; Found: 596.8(M+H).

Example 5[7-Iodo-3-(4-isopropyl-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 0.6H), 10.40 (s, 0.4H), 7.63-6.54(m, 12H), 6.30 (br s, 1 H), 5.64(s, 0.4H), 5.08 (s, 0.6H), 2.60 (m, 1H),0.96 (m, 6H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₃N₂O₄I:554.1; Found: 554.9(M+H).

Example 6[2,5-Dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 0.6H), 10.2 (s, 0.4H), 7.7-6.9(m, 13H), 6.42 (s, 0.4H), 6.39 (s, 0.6H), 5.86 (s, 0.4H), 5.30 (s,0.6H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₇F₃N₂O₄: 454.1; Found:455.0(M+H).

Example 72-[7-Iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl-3-phenyl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 0.6H), 10.56 (s, 0.4H), 7.70-7.10(m, 11H), 6.55 (m, 1H), 5.79 (s, 0.6H), 5.59 (br s, 0.6H), 5.51 (s,0.4H), 5.31 (br s, 0.4H), 3.35 (m, 2H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₅H₁₈F₃N₂O₄I: 594.0; Found: 595.0(M+H).

Example 8(7-Iodo-2,5-dioxo-3-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 0.6H), 10.47 (s, 0.4H), 7.78-6.79(m, 12H), 6.63 (d, J=8.3 Hz, 0.6H), 6.54 (d, J=83 Hz, 0.4H), 6.38 (s,0.6H), 6.34 (s, 0.4H), 5.83 (s, 0.4H), 5.23 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₁₇N₂O₄I: 512.0; Found: 513.0(M+H).

Example 9[7-Iodo-2,5-dioxo-3-(3-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.6H), 10.53 (s, 0.4H), 7.81-6.90(m, 11H), 6.61 (d, J=8.7 Hz, 0.6H), 6.54 (d, J=8.6 Hz, 0.4H), 6.40 (s,0.6H), 6.36 (s, 0.4H), 5.78 (s, 0.4H), 5.40 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₄H₁₆F₃N₂O₄I: 580.0; Found: 580.8(M+H).

Example 10(7-Iodo-2,5-dioxo-3-p-tolyl-1,2,3,5-tetrahydrobenzo[e][1.4]diazepin-4-yl)-phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 0.6H), 10.45 (s, 0.4H). 7.78-6.54(m, 11H), 6.37 (s, 0.6H), 6.30 (s, 0.4H), 5.77 (s, 0.4H), 5.16 (s,0.6H), 5.12 (s, 1H), 2.05 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd.for C₂₄H₁₉N₂O₄I: 526.0; Found: 526.8(M+H).

Example 11[7-Iodo-3-(4methoxy-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 0.6H), 10.44 (s, 0.4H), 7.78-6.54(m, 12H), 6.37 (s, 0.6H), 6.30 (s, 0.4H), 5.72 (s, 0.4H), 5.16 (s,0.6H), 3.61 (s, 1H), 3.55 (s, 2H). Mass spectrum (LCMS, ESI pos) Calcd.for C₂₄H₁₉N₂O₅I: 542.0; Found: 542.8(M+H).

Example 12(7-Iodo-3-naphthalen-2-yl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 0.75H), 10.72 (s, 0.25H),8.01-7.00 (m, 14H), 6.62 (d, J=8.3 Hz, 0.75H), 6.57 (d, J=8.3 Hz,0.25H), 6.44 (s, 0.75H), 6.21 (s, 0.25H), 5.52 (s, 0.25H), 5.26 (s,0.75H). Mass spectrum (LCMS. ESI pos) Calcd. for C₂₇H₁₉N₂O₄I: 562.0;Found: 562.9(M+H).

Example 13[3-(4-tert-Butyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 0.6H), 10.41 (s, 0.4H, 7.78-6.54(m, 12H), 6.32 (s, 0.6H), 6.27 (s, 0.4H), 5.76(s, 0.4H), 5.13 (s, 0.6H),1.12(s, 3 H), 1.07 (s, 6H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₇H₂₅N₂O₄I: 568.1; Found: 568.9(M+H).

Example 14[3-(2-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 0.41H), 10.53 (s, 0.6H),7.81-6.90 (m, 11H), 6.72 (s, 0.4H), 6.61 (d, J=8.7 Hz, 0.4H), 6.54 (d,J=8.6 Hz, 0.6H), 6.36 (s, 0.6H), 5.22 (s, 0.6H), 5.12 (s, 0.4H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₆N₂O₄ICl: 546.0; Found:547.8(M+H).

Example 15[3-(3-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 0.6H), 10.53 (s, 0.4H), 7.79-6.76(m, 11H), 6.65 (d, J=8.7 Hz, 0.6H), 6.56 (d, J=8.6 Hz, 0.4H), 6.34 (s,0.6H), 6.31 (s, 0.4H), 5.72 (s, 0.4H), 5.25 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₁₆N₂O₄I: 546.0; Found: 546.9(M+H).

Example 16[3-(4-Benzyloxy-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 0.7H), 10.47 (s. 03H), 7.78-6.56(m, 17H), 6.35 (s, 0.7H), 6.28 (s, 0.3H), 5.66 (s, 0.3H), 5.13 (s,0.7H), 4.95 (s, 0.5H), 4.89 (s, 1.5H). Mass spectrum (LCMS, ESI pos)Calcd. for C₃₀H₂₃N₂O₅I: 618.1; Found: 618.8(M+H).

Example 17[7-Iodo-2,5-dioxo-3-(4-phenoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 0.5H), 10.41 (s, 0.5H), 7.80-6.5(m, 17H), 6.33 (s, 0.5H), 5.88 (s, 0.5H), 536 (s, 0.5H), 5.22 (s, 0.5H).Mass spectrum (LCMS, ESI pos) Calcd. for C₂₉H₂₁N₂O₅I: 604.0; Found:604.8(M+H).

Example 18[7-Iodo-2,5-dioxo-3-(2-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 0.5H), 10.61 (s, 0.5H), 7.81-6.54(m, 12H), 6.40 (s, 0.5H), 5.35 (s, 0.5H), 5.29 (s, 0.5H), 5.08 (s,0.5H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₆F₃N₂O₄I: 580.0;Found: 580.9(M+H).

Example 193-(3,4-Dichloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 0.8H), 10.58 (s, 0.2H), 7.81-6.84(m, 10H), 6.67 (d, J=8.5 Hz, 0.8H), 6.58 (d, J=8.5 Hz, 0.2H), 6.33 (s,0.8H), 6.31 (s, 0.2H), 5.35 (s, 0.2H), 5.24 (s, 0.8H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₁₅N₂O₄ICl₂: 579.9; Found: 580.8(M+H).

Example 20(3-(3,4-Dimethoxy-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 0.5H), 10.41 (s, 0.5H), 7.81-7.22(m, 10H), 6.67 (d, J=8.4 Hz, 0.5H), 6.55 (d, J=8.5 Hz, 0.5H), 6.42 (s,0.5H), 6.12 (s, 0.5H), 5.62 (s, 0.5H) 5.30 (s, 0.5H), 3.54 (s, 3H), 3.43(s, 3H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₅H₂₁N₂O₆I: 572.0;Found: 572.8(M+H).

Example 21[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 0.7H), 10.46 (s, 0.3H), 7.78-6.47(m, 11H), 6.32 (s, 0.8 H), 6.25 (s, 0.8H), 6.23 (s, 0.2H), 5.10 (s,0.2H), 4.07 (br s. 4H). Mass spectrum (LCMS, ESI pos) Calcd forC₂₅H₁₉N₂O₆I: 570; Found: 570.90 (M+H).

Example 22[3-(4-Bromo-2-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 0.6H). 10.47 (s, 0.4H), 7.81-7.01(m, 10H), 6.67 (d, J=8.7 Hz, 0.6H), 6.58 (d, J=8.6 Hz, 0.4H), 6.26 (s,0.4H), 6.13 (s, 0.6H) 5.77 (s, 0.4H), 5.14 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₁₅N₂O₄IBrF: 607.9; Found: 608.8(M+H).

Example 23[3-(2-Fluoro-4-trifluoromethyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.8H), 10.47 (s, 0.2H). 7.81-6.81(m, 10H), 6.66 (d, J=8.4 Hz, 0.8H), 6.56 (d, J=8.4 Hz, 0.2H), 6.31 (s,0.2H), 6.16 (s, 0.8H) 6.02 (s, 0.2H), 5.29 (s, 0.8H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₄H₁₅N₂O₄IF₄: 598.0; Found: 598.9(M+H).

Example 24[3-(3-Fluoro-4-trifluoromethyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.82 (s, 0.8H), 10.61 (s, 0.2H), 7.81-6.90(m, 10H), 6.65 (d, J=8.5 Hz, 0.8), 6.58 (d, J=85 Hz, 0.2H), 6.31 (s,0.2H), 6.29 (s, 0.8H) 5.74 (s, 0.2H), 5.29 (s, 0.8H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₄H₁₅N₂O₄IF₄: 598.0; Found: 598.9(M+H).

Example 25[3-(4-Chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 0.8H), 10.57 (s, 0.2H), 7.81-6.60(m, 11H), 6.27 (s, 1H), 5.67 (s, 0.2H), 5.22 (s, 0.8H). Mass spectrum(LSMS, ESI pos) Calcd. for C₂₃H₁₅N₂O₄IClF: 564.0; Found: 564.9(M+H).

Example 26[3-(4-Bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.6H), 10.57 (s, 0.4H), 7.80-6.82(m, 11H), 6.64 (d, J=8.6 Hz, 0.6H), 6.54 (d, J=8.6 Hz, 0.4H), 6.32 (s,0.6H), 6.27 (s, 0.4H) 5.58 (s, 0.4H), 5.10 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₁₆N₂O₄IBr: 589.9; Found: 591.8(M+H).

Example 27[8-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 0.8H), 10.58 (s, 0.2H), 7.53-6.83(m, 12H), 6.34 (s, 0.8H), 6.30 (s, 0.2H), 5.66 (s, 0.2H), 5.14 (s,0.8H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₆N₂O₄Cl₂: 454.0;

Found: 454.9(M+H).

Example 28[7-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 0.7H), 10.58 (s, 0.3H), 7.50-6.77(m, 12H), 6.34 (s, 0.7H), 6.31 (s, 0.3H), 5.69 (s, 0.3H), 5.15 (s,0.7H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₆N₂O₄ICl₂: 454.0;Found: 454.9(M+H).

Example 29[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (t, 0.7H), 10.61 (s, 0.3H), 7.59-6.92(m, 11H), 6.80 (d, J=8.6 Hz, 0.7H), 6.72 (d, J=8.6 Hz, 0.3H), 6.33 (s,0.7H), 6.29 (s, 0.3H) 5.60 (s, 0.3H), 5.13 (s, 0.7H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₂₆N₂O₄ClBr. 498.0; Found: 499.1 (M+H).

Example 30[3-(4-Chloro-phenyl)-7-methoxy-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.52 (s, 0.7H), 10.33 (a, 0.3H), 7.50-6.81(m, 11H), 6.75 (d, J=8.9 Hz, 0.7H), 6.68 (d, J=8.9 Hz, 0.3H), 6.32 (s,0.7H), 6.29 (s, 0.3H) 5.47 (s, 0.3H), 5.11 (s, 0.7H), 3.64 (s, 3H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₉N₂O₅Cl: 450.1; Found:450.9(M+H).

Example 313-(4-Chloro-phenyl)-7-methyl-2,5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 0.6H), 10.39 (s, 0.4H), 7.50-6.85(m, 11H), 6.72 (d, J=8.1 Hz, 0.7H), 6.65 (d, J=8.1 Hz, 0.3H), 6.33 (s,0.7H), 6.29 (s, 0.3H) 5.55 (s, 0.3H), 5.14 (s, 0.7H), 2.14 (s, 2H), 2.13(s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₉N₂O₄Cl: 434.1;

Found: 435.0(M+H).

Example 32[3-(4-Chloro-phenyl)-2,5-dioxo-1,2,5-tetrahydro-naphtho[2,3-e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.87 (s, 0.6H). 10.71 (s, 0.4H), 8.21-6.98(m, 12H), 6.38 (s, 0.6H), 6.32 (s, 0.4H) 5.52 (s, 0.4H), 5.20 (s, 0.6H)2.14 (s, 2H) 2.13 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₇H₁₉N₂O₄Cl: 470.1; Found: 471.0(M+H).

Example 33[8-Chloro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.9H), 10.55 (s, 0.1H), 7.53-6.80(m, 12H), 6.32 (s, 1H), 5.18 (s, 1H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₄H₁₆N₂O₅Cl₂F₃: 504.1; Found: 505.0(M+H).

Example 34[7-Chloro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 0.5H), 10.59 (s, 0.5H), 7.50-7.00(m, 11H), 6.85 (d, J=8.8 Hz, 0.5H), 6.77 (d, J=8.8 Hz, 0.5H), 6.32 (s,1H), 5.67 (s, 0.5H), 5.18 (s, 0.5H). Mass spectrum (LCMS, ESI pos) Calcdfor C₂₄H₁₆N₂O₅ClF₃: 504.1; Found: 504.9(M+H).

Example 35[7-Bromo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 0.9H), 10.56 (s, 0.1H), 7.58-6.98(m, 11H), 6.79 (d, J=85 Hz, 0.9H), 6.70 (d, J=8.5 Hz, 0.1H), 6.33 (s,1H), 5.75 (s, 0.1H), 5.20 (s, 0.9H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₄H₁₆N₂O₅BrF₃: 548.0; Found: 548.8(M+H).

Example 36[7-Methoxy-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.52 (s, 0.6H), 10.30 (s, 0.4H), 7.52-6.79(m, 11H), 6.74 (d, J=8.8 Hz, 0.6H), 6.66 (d, J=8.8 Hz, 0.4H), 6.33 (s,0.4H), 6.30 (s, 0.6H) 5.56 (s, 0.4H), 5.16 (s, 0.6H), 3.62 (s, 3H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₅H₁₉N₂O₆F₃: 500.1; Found:500.9(M+H).

Example 37[7-Methyl-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 0.6H), 10.41 (s, 0.4H), 7.51-7.00(m, 11H), 6.71 (d, J=8.2 Hz, 0.6H), 6.64 (d, J=8.2 Hz, 0.4H), 6.30 (s,1H), 5.51 (s, 0.4H), 5.16 (s, 0.6H), 2.11 (s, 2H), 2.10 (s, 1H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₅H₁₉N₂O₅F₃: 484.1; Found:485.0(M+H).

Example 38[2,5-Dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-naphtho[2,3-e][1,4]diazepin-4yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 0.8H), 10.51 (s, 0.2H), 7.72-6.90(m, 15H), 6.37 (s, 1H), 5.57 (s, 0.4H), 5.25 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₈H₁₉N₂O₅F₃: 520.1; Found: 521.0(M+H).

Example 392-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.6H), 10.51 (s, 0.4H), 7.72-6.95(m, 11H), 6.57 (d, J=8.9 Hz, 0.4H), 6.54 (d, J=8.9 Hz, 0.6H), 5.57 (brs, 1H), 5.39 (s, 0.6H) 5.28 (s, 0.4H), 3.41 (d, J=4.2 Hz, 0.8H), 3.37(d, J=4.2 Hz, 1.2H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₄H₁₈N₂O₄ICl: 560.0; Found: 560.8(M+H).

Example 403-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.8H), 10.54 (s, 0.2H), 7.72-6.95(m, 10H), 6.58(d, J=8.4 Hz, 0.2H), 6.54 (d, J=8.4 Hz, 0.8H), 5.54 (br s,1.4H), 5.35 (s, 0.2H), 5.13 (s, 0.4H), 3.41 (d, J=44 Hz, 0.8H), 3.37 (d,J=4.4 Hz. 1.2H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₇N₂O₄Cl₂:594.0; Found: 594.8 (M+H).

Example 412-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-(4-hydroxy-phenyl)propionicacid

1H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 0.9H), 10.5 (s, 0.1H), 9.16 (s,0.1H), 9.11 (s, 0.9H), 7.71 (s, 0.2H), 7.62 (d, J=1.9 Hz, 0.8H), 7.49(m, 1H), 7.15-6.96 (m, 6H), 6.57(m, 3H), 5.63 (br s, 0.8H), 5.46 (br s,0.8H), 5.21 (br s, 0.4H), 3.25 (m, 2H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₄H₁₈N₂O₅ICl: 576.0; Found: 576.8(M+H).

Example 422-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3cyclohexyl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 0.9H), 10.84 (s, 0.1H), 7.76 (d,J=2.1 Hz, 1H), 7.57 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H),7.12 (d, J=8.4 Hz, 2H), 6.61 (d, J=8.6 Hz, 1H), 5.51 (br s, 1H), 5.43(s, 1H), 1.87-0.83(m, 13H), 3.23 (d, J=5.1 Hz, 1H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₄H₂₄N₂O₄ICl: 566.0; Found: 566.9(M+H).

Example 432-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 0.8H), 10.52 (s, 0.2H), 7.72-6.95(m, 11H), 6.57 (d, J=8.6 Hz, 0.2H), 6.52 (d, J=8.6 Hz, 0.8H), 5.58 (brs, 1.2H), 5.44 (s, 0.4H), 5.29 (s, 0.4H), 3.42 (d, J=5.5 Hz, 0.8H), 3.39(d, J=5.5 Hz, 1.2H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₅H₁₈N₂O₅IF₃: 610.0; Found: 610.9(M+H);

Example 443-(4-Chloro-phenyl)-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 0.811), 10.54 (s, 0.2H),7.72-6.95 (m, 10H), 6.57(d, J=8.6 Hz, 0.2H), 6.52 (d, J=8.6 Hz, 0.8H),5.59 (br s, 1.4H), 5.54 (s, 0.2H), 5.40 (s, 0.2H), 5.16 (s, 0.2H), 3.42(d, J=5.2 Hz, 0.8H), 3.39 (d, J=5.2 Hz, 1.2H). Mass spectrum (LCMS, ESIpos) Calcd. for C₂₅H₁₇N₂O₅IF₃: 644.0; Found: 644.8(M+H).

Example 453-(3-Hydroxy-phenyl)-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 9.15 (s, 1H), 7.60 (d, J=1.6Hz, 4H), 7.48 (dd, J=1.9 Hz, 8.4 Hz, 3H), 7.05 (m, 3H), 6.59 (d, J=8.5Hz, 0.6H), 6.54 (d, J=8.5 Hz, 0.4H), 5.53 (br s, 2H), 3.28 (m, 2H). Massspectrum. (LCMS, ESI pos) Calcd. for C₂₅H₁₈N₂O₆IF₃: 626.0; Found:626.9(M+H).

Example 463-Cyclohexyl-2-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 0.9H), 10.84 (s, 0.1H), 7.71 (d,J=1.9 Hz, 1H), 7.54 (dd, J=2.1 Hz, 8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H),7.14 (d, J=8.4 H, 2H), 6.59 (d, J=8.6 Hz, 1H), 5.51 (br s, 2H),1.87-0.83 (m, 13H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₅H₂₄N₂O₅IF₃: 616.1; Found: 616.9(M+H).

Example 47[1-Benzyl-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.62-6.97 (m, 17H), 6.22 (s, 0.6H), 6.19(s, 0.4H), 5.65 (br s, 1H), 5.40 (m, 1H), 4.80 (m, 1H). Mass spectrum(LCMS, ESI pos) Calcd. for C₃₀H₂₂N₂O₄ICl: 636.0; Found: 636.9(M+H).

Example 48[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-phenethyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, CDCl₃): δ 7.71 (s, 1H), 7.56 (m, 2H), 7.31 (m, 8H),7.05 (m, 5H), 6.89 (s, 1H), 6.20 (s, 1H), 5.85 (s, 0.4H), 5.31 (s,0.6H), 4.23 (m, 1H), 3.85 (m, 1H), 2.85 (m, 0.5H), 2.62 (m, 1.5H). Massspectrum (LCMS, ESI-pos) Calcd. for C₃₁H₂₄N₂O₄ICl: 650.0; Found:650.9(M+H).

Example 49[3-(4-Chloro-phenyl)-7-iodo-1-isobutyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (m, 1H), 7.59 (m, 1H), 7.51 (d, J=6.5Hz, 1H), 7.39 (m, 5H), 7.12 (m, 1H), 6.95 (m, 3H), 6.26 (s, 0.6H), 6.13(s, 0.4H), 5.57 (s, 0.6H), 5.34 (s, 0.4H), 4.10 (m, 2H), 1.60 (m, 1H),0.65 (m, 6H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₂₄N₂O₄ICl:602.0;

Found: 602.9(M+H).

Example 50[3-(4-Chloro-phenyl)-7-iodo-(3-methylbutyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (m, 1H), 7.53 (m, 2H), 7.30 (m, 4H),7.06 (m, 3H), 6.87 (m, 1H), 6.26 (s, 1H), 6.04 (m, 1.6H), 535 (s, 0.4H),4.07 (m, 1H), 3.44 (m, 1H), 1.40 (m, 1H), 1.24 (m, 1H), 1.13 (m, 1H),0.75 (m, 6H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₈H₂₆N₂O₄Cl:616.1;

Found: 616.9(M+H).

Example 51[3-(4-Chloro-phenyl)-1-cyclobutylmethyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (m, 1H), 7.58 (m, 1H), 7.49 (m, 2),7.40 (m, 4H), 7.11 (m, 2H), 6.95 (m, 2H), 6.23 (s, 0.7H), 6.10 (s,0.7H), 5.56 (s, 0.3H), 5.33 (s, 0.3H), 4.18 (m, 1H), 3.52 (m, 1H), 2.19(m, 1H), 1.68 (m, 4H), 1.40 (m, 2H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₈H₂₄N₂O₄ICl: 614.0; Found: 614.9(M+H).

Example 52[3-(4-Chloro-phenyl)-1-cyclopentylmethyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (m, 1H), 7.53 (m, 3H), 7.38 (s, 1H),7.25 (s, 4H), 7.02 (m, 3H), 6.85 (m, 1H), 6.34 (s, 0.7H), 6.10 (br s,1H), 5.44 (s, 0.3H), 4.02 (m, 1.3H), 3.48 (m, 0.7H), 1.34 (m, 6H), 0.77(m, 2H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₉H₆N₂O₄ICl: 628.1; Found:628.9(M+H).

Example 53[3-(4-Chloro-phenyl)-1-cyclohexylmethyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.64 (m, 1H), 7.53 (m, 3H), 7.35 (s, 1H),7.27 (s, 4H), 7.05 (m, 2H), 6.85 (m, 1H), 6.34 (s, 0.7H), 6.06 (br s,1H), 5.47 (s, 0.3H), 4.98 (m, 0.7H), 3.23 (m, 1.3H), 1.53-0.6 (m, 11H).Mass spectrum (LCMS, ESI pos) Calcd. for C₃₀H₂₈N₂O₄ICl: 642.9; Found643.0(M).

Example 54[3-(4-Chloro-phenyl)-7-iodo-1-(2-methyl-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (s, 0.4H), 7.60 (s, 0.6H), 7.51 (d,J=7.4 Hz, 1H), 7.44 (m, 1H), 7.38 (s, 1H), 7.26 (m, 4H), 7.05 (m, 6H),6.87 (m, 2H), 6.29 (s, 0.7H), 6.17 (s, 1H), 5.55 (s, 0.3H), 5.34 (d,J=15.8 Hz, 0.3H), 5.27 (d, J=15.8 Hz, 0.7H), 4.93 (d, J=15.8 Hz, 0.3H),4.68 (d, J=15.8 Hz, 0.7H), 2.20 (s, 1H), 1.98 (s, 2H). Mass spectrum(LCMS, ESI pos) Calcd. for C₃₁H₂₄N₂O₄ICl: 650.0; Found: 650.9(M+H).

Example 55[3-(4-Chloro-phenyl)-7-iodo-1-(3-methyl-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.62 (s, 0.4H), 7.59 (s, 0.6H), 7.52 (d,J=7.0 Hz, 1H), 7.45 (m, 3H), 7.26 (m, 3H), 7.09 (m, 5H), 6.90 (m, 3H),6.74 (s, 0.6H), 6.34 (s, 0.4H), 6.17 (m, 1H), 5.53 (d, J=15.6 Hz, 0.4H),5.27 (d, J=15.6 Hz, 0.6H), 4.83 (d, J=15.6 Hz, 0.4H), 4.64 (d, J=15.6Hz, 0.6H), 2.18 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd. forC₃₁H₂₄N₂O₄ICl: 650.0; Found: 650.9(M+H).

Example 56[3-(4-Chloro-phenyl)-7-iodo-1-(4-methyl-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.57 (m, 1H), 7.43 (m, 3H), 7.31 (m, 4H),7.10 (m, 3H), 6.99 (m, 3H), 6.84 (m, 2H), 6.35 (s, 4H), 6.19(s, 1H),5.55 (d, J=15.1 Hz, 0.4H), 5.42 (s, 0.6H), 5.27 (d, J=15.1 Hz, 0.6H),4.77 (d, J=15.1 Hz, 0.4H), 4.59 (d, J=15.1 Hz, 0.6H), 2.20 (s, 3H). Massspectrum (LCMS, ESI pos) Calcd. for C₃₁H₂₄N₂O₄ICl: 650.0; Found:650.9(M+H).

Example 57[3-(4-Chloro-phenyl)-7-iodo-1-naphthalen-2-ylmethyl-2.5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (m, 4H), 7.58 (m, 2H), 7.46 (m, 4H),7.31 (m, 2H), 7.15 (s, 2H), 7.05 (m, 1H), 6.90 (m, 1H), 6.36 (m, 0.6H),6.23 (s, 1H), 5.76 (d, J=15.8 Hz, 0.4H), 5.47 (d, J=15.8 Hz, 0.6H), 5.44(s, 0.4H), 5.00 (d, J=15.8 Hz, 0.4H), 4.84 (d, J=15.8 Hz, 0.6H), 2.20(s, 3H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₃₄H₂₄N₂O₄ICl: 686.0; Found:686.9(M+H).

Example 58[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-pyridin-2-ylmethyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (m, 1H), 7.73 (m, 2H), 7.65 (m, 2H),7.53 (m, 4H), 7.34 (m, 4H), 7.09 (m, 2H), 6.90 (m, 1H), 6.32 (s, 0.6H),6.20 (s, 1H), 5.89 (br s, 0.4H), 5.36-4.89 (m, 2H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₉H₂₁N₃O₄ICl: 637.0; Found: 638.0(M+H).

Example 59[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-pyridin-3-ylmethyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (m, 1H), 7.52 (m, 3H), 7.27 (m, 4H),7.11 (m, 4H), 6.96 (m, 2H), 6.82 (m, 2H), 6.33 (s, 0.6H), 6.24 (s,0.4H), 6.15 (s, 0.6H), 5.69 (m, 0.4H), 5.35 (s, 0.6H), 5.31 (m, 0.4H),4.85 (m, 1H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₉H₂₁N₃O₄ICl: 637.0; Found:638.1(M+H).

Example 60[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-pyridin-4-ylmethyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (br s, 1H), 7.64 (m, 1H), 7.48 (m,4H), 7.32 (m, 4H), 7.11 (m, 3H), 6.91 (m, 3H), 6.34 (s, 0.6H), 6.23 (s,0.4H), 6.16 (s, 0.4H), 5.60 (d, J=15.5 Hz, 0.4H), 5.38 (s, 0.6H), 5.26(d, J=15.5 Hz, 0.6H), 4.90 (d, J=15.5 Hz, 0.4H), 4.77 (d, J=15.5 Hz,0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₉H₂₁N₃O₄ICl: 637.0;Found: 638.1(M+H).

Example 61(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid methyl ester

¹H NMR (400 MHz, CDCl₃): δ 8.04 (m, 1.7H), 7.87.(m, 0.3H), 7.50 (s, 1H),7.42-7.10 (m, 6H), 7.00 (m, 1H), 6.83 (s, 0.8H), 6.73 (d, J=8.4 Hz,1.2H), 6.44 (d, J=8.4 Hz, 0.8H), 6.37 (d, J=8.4 Hz, 0.2H), 5.34 (m,0.2H), 5.28 (s, 0.8H), 3.84 (s, 0.6H), 3.83 (s, 2.4H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₄H₁₇N₂O₄ICl₂: 594.0; Found: 594.8(M+H).

Example 62(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 0.6H), 10.53 (s, 0.4H), 7.81 (s,0.6H) 7.73 (s, 0.4H), 7.52-7.15 (m, 4H), 7.07 (d, J=7.9 Hz, 3H), 6.81(m, 2H), 6.63 (d, J=8.6 Hz, 0.6H), 6.54 (d, J=8.6 Hz, 0.4H), 6.25 (m,1H), 5.81 (br s, 0.4H), 5.22 (s, 0.6H). Mass spectrum (LCMS, EST pos)Calcd. for C₂₃H₁₅N₂O₄ICl₂: 579.9; Found: 580.8(M+H).

Example 63[3-(4-Chloro-phenyl)-7-iodo-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.63 (m, 2H), 7.49 (m, 1H), 7.29 (m, 4H),7.09 (s, 2H), 7.00 (d, J=7.7 Hz, 1H), 6.82 (m, 1H), 6.72 (m, 1H), 6.28(m, 1H), 5.92 (s, 0.5H) 5.31 (s, 0.5H), 3.12 (s, 3H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₄H₁₈N₂O₄ICl: 560.0; Found: 560.9(M+H).

Example 64[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1-(3-phenyl-propyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.70 (m, 1H), 7.49 (m, 3H), 7.17 (m, 11H),6.80 (s, 2H), 6.36 (m, 0.6H), 6.15 (s, 0.4H), 6.01 (s, 0.6H), 5.31 (s,0.4H), 4.50 (m, 1H), 4.34 (m, 1H), 2.31 (m, 1H), 2.24 (m, 1H), 1.58, (m,1H), 1.45 (m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. forC₃₂H₂₆N₂O₄ICl: 664.1; Found: 665.2(M+H).

Example 652-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-methyl-butyricacid

¹H NMR (400 MHz, DMSO-d₆): δ 7.80-7.75 (m, 1H), 7.58-7.40 (m, 5H),7.17-7.11 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H),6.67-6.52 (m, 2H), 5.15 (s, 0.5 H), 4.94 (s, 0.5H), 4.07-3.95 (m, 1H),2.05 (s, 1H), 0.84 (d, J=6 Hz, 3H), 0.79-0.71 (m, 3H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₈H₂₄Cl₂IN₃O₅: 679.01; Found: 679.69 (M+H).

Example 663-[3-(4-Chloro-phenyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-propionicacid

¹H NMR (400 MHz, DMS-d₆): δ 10.90 (s, 0.8H), 10.71 (s, 0.2H), 7.81 (s,1H) 7.66 (m, 1H), 7.61-7.53 (m, 3H), 7.42-7.27 (m, 4H), 6.99 (d, J=8.8Hz, 1.6 H), 6.61 (d, J=8.7 Hz, 0.4H), 6.50 (m, 2H), 5.24 (s, 1H), 3.18(m, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₈N₂O₄ICl: 560.0;Found: 560.9(M+H).

Example 672-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-methyl-2-phenyl-acetamide

¹H NMR (400 MHz, CDCl₃): δ 8.06 (d, J=2.1 Hz, 0.8H), 8.02 (m, 0.6H),7.98 (s, 0.6H), 7.50-7.30 (m, 6H), 7.16-7.07 (m, 4H), 6.50 (m, 1H), 6.34(d, J=8.4 Hz, 1H), 5.96 (m, 0.5H), 5.61 (s, 0.5H), 2.91 (s, 1.5H), 2.90(s, 1.5H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₉N₃O₃ICl:559.0; Found: 559.9(M+H).

Example 68(7-Iodo-2,5-dioxo-3-pyridin-2-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 0.6H), 10.52 (s, 0.4H), 8.56 (m,0.4H), 8.46 (m, 0.6H), 8.06 (s, 0.4H), 7.85 (m, 1H), 7.76 (dd, J=2.2 Hz,8.2 Hz, 1H), 7.61 (m, 0.6H), 7.51 (m, 1H), 7.40 (m, 2H), 7.30 (m, 1H),7.10 (m, 2H), 6.70 (m, 2H), 6.63 (d, J=8.6 Hz, 0.6H), 6.56 (d, J=8.6 Hz,0.4H), 5.67 (s, 0.4H), 5.58 (s, 0.6H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₂H₁₆N₃O₄I: 513.0; Found: 514.0(M+H).

Example 69(7-Iodo-2,5-dioxo-3-pyridin-3-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 0.5H), 10.36 (s, 0.5H), 8.33 (m,1H), 8.35-7.00 (m, 10H), 6.63 (d, J=8.6 Hz, 0.6H), 6.56 (d, J=8.6 Hz,0.4H), 6.35 (s, 1H), 5.82 (s, 0.4H), 5.30(s, 0.6H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₂H₁₆N₃O₄I: 513.0; Found: 514.1(M+H).

Example 70(7-Iodo-2,5-dioxo-3-thiophen-3-yl-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl)-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 0.9H), 10.43 (s, 0.1H), 7.78 (s,1H), 7.54 (m, 3H), 7.35 (m, 4H), 7.15 (m, 1H), 6.72 (m, 1H), 6.38 (s,1H), 6.30 (s, 1H), 5.15 (s, 0.1H), 5.12 (s, 0.9H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₁H₁₅N₂O₄IS: 518.0; Found: 518.9(M+H).

Example 71[7-Iodo-3-5-methyl-thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 7.83 (s, 1H), 7.61 (m, 1H),7.45 (m, 2H), 7.33 (m, 3H), 6.76 (d, J=8.6 Hz, 1H), 6.33 (s, 1H), 6.23(m, 1H), 6.02 (s, 1H), 5.24 (s, 1H), 2.11 (s, 3H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₂H₁₇N₂O₄IS: 532.0; Found: 532.9(M+H).

Example 72[7-Iodo-3-(3-methyl-thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 7.99 (s, 1H), 7.68 (m, 1H),7.34 (m, 4H), 7.00 (m, 1H), 6.77 (m, 1H), 6.39 (m, 1H), 6.27 (s, 1H),6.02 (s, 1H), 5.36 (s, 1H), 1.69 (s, 3H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₂H₁₇N₂O₄IS: 532.0; Found: 532.8(M+H).

Example 73[3-(4-Bromo-thiophen-2-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 0.7H), 10.57 (s, 0.3H). 7.83 (d,J=2.2 Hz, 0.7H), 7.77 (d, J=2.2 Hz, 0.3H), 7.65 (m, 1H), 7.47 (d, J=7.0Hz, 2H), 7.33 (m, 4H), 7.00 (m, 1H), 6.78 (d, J=8.6 Hz, 0.7H), 6.68 (d,J=8.6 Hz, 0.3H), 6.36 (s, 0.7H), 6.24 (s, 0.3H), 5.87 (s, 0.3H), 5.32(s, 0.7H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₁H₁₄N₂O₄ISBr: 595.9; Found:596.8(M+H).

Example 74(3-[2,2′]Bithiophenyl-5-yl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 0.8H), 10.57 (s, 0.2H), 7.86 (d,J=2.0 Hz, 0.8H), 7.79 (d, J=2.0 Hz, 0.2H), 7.63 (m, 1H), 7.52 (d, J=7.4Hz, 2H), 7.39 (m, 5H), 7.01 (m, 1H), 6.79 (m, 2H), 6.40 (s, 1H), 6.27(m, 1H), 5.88 (s, 0.2H), 5.30 (s, 0.8H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₅H₁₇N₂O₄IS₂: 600.0; Found: 601.9(M+H).

Example 75[7-Iodo-3-(3-methyl-benzo[b]thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 0.5H), 10.56 (s, 0.5H), 8.00 (s,1H), 7.69 (m, 2H), 7.46 (m, 2H), 7.26 (m, 4H), 6.94 (m, 1H), 6.77 (m,1H), 6.70 (s, 0.5H), 6.63 (d, J=8.6 Hz, 1H), 6.28 (s, 0.5H), 5.60 (s,0.5H), 5.48 (s, 0.5H), 1.90 (s, 3H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₆H₁₉N₂O₄IS: 582.0; Found: 583.9(M+H).

Example 76{3-[5-(2-Chloro-phenyl)-furan-2-yl]-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 0.8H), 10.9 (s, 0.2H), 7.90 (d,J=2.1 Hz, 1H), 7.70 (dd, J=2.1 Hz, 8.3 Hz, 2H), 7.37 (m, 5H), 6.85 (m,4H), 6.67 (d, J=3.5 Hz 1H), 6.41 (s, 1H), 5.62 (s, 1H), 5.32 (s, 1H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₁₈N₂O₅ICl: 612.0, Found:613.1(M+H).

Example 77{3-[5-(3-Chloro-phenyl)-furan-2-yl]-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 7.91 (d, J=23 Hz, 2H), 7.68(dd, J=2.1 Hz, 8.3 Hz, 2H), 7.49 (d, J=7.2 Hz, 2H), 7.30 (m, 5H), 6.89(d, J=8.6 Hz, 1H), 6.63 (d, J=3.5 Hz, 1H), 6.44 (s, 1H), 5.49 (s, 1H),5.35 (s, 1H.). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₁₈N₂O₅ICl:612.0; Found: 612.9(M+H).

Example 78(7-Iodo-2,5-dioxo-3-quinolin-3-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 0.8H), 10.61 (s, 0.2H), 9.02 (d,J=2.0 Hz, 1.5 H), 8.82 (d, J=2.0 Hz, 0.5H), 8.45 (s, 1.5 H), 8.36 (s,0.5H), 8.05 (d, J=8.5 Hz, 1.5H), 7.98 (d, J=8.5 Hz, 0.5H), 7.84-6.84 (m,7H), 6.72 (s, 0.8H), 6.62 (d, J=8.6 Hz, 0.8H), 6.56 (d, J=8.6 Hz, 0.2H),6.45 (s, 0.2H), 5.68 (s, 0.2H), 5.10 (s, 0.8H.). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₆H₁₈N₃O₄I: 563.0; Found: 564.1(M+H).

Example 79[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 0.5H), 10.63 (s, 0.5H), 7.58 (m,1H) 7.52 (d, J=8.6 Hz 1H), 7.41 (m, 4H), 7.17 (m, 3H), 6.98 (m, 1H),6.79 (d, J=8.6 Hz, 0.5H), 6.72 (d, J=8.6 Hz, 0.5H), 6.29 (s, 0.5H), 6.24(s, 0.5H), 5.68 (s, 0.5H), 5.23 (s, 0.5H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₃H₁₅N₂O₄BrCl₂: 534.0; Found: 534.9(M+H).

Example 802-[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-(4-trifluoromethyl-phenyl)-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 0.8H), 10.51 (s, 0.2H), 7.30-7.20(m, 6H), 7.35 (m, 1H), 7.15 (m, 3H), 6.96 (m, 2H), 6.72 (m, 1H), 5.60(br s, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₅H₁₇N₂O₄BrF₃Cl:580.0; Found: 581.0(M+H).

Example 812-[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 0.8H), 10.56 (s, 0.2H), 7.48 (s,1H) 7.42-7.30 (m, 4H), 7.22 (m, 3H), 7.13 (m, 2H), 6.95 (m, 1H), 6.69(m, 1H), 5.54(m, 1.4H), 5.40 (s, 0.3H), 5.30 (br s, 0.3H), 3.40 (m,1.5H), 3.20 (m, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₄H₁₈N₂O₄BrCl: 512.0; Found: 513.0(M+H).

Example 822-[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-(4-chloro-phenyl)-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 0.8H), 10.58 (s, 0.2H), 7.50 (s,1H), 7.43-7.37 (m, 3H), 7.22-7.12 (m, 4H), 6.92 (m, 2H), 6.69 (m, 1H),5.57(m, 0.8H), 5.53 (s, 0.8H), 5.37 (s, 0.2H), 5.16 (br s, 0.2H), 3.40(m, 1.5H), 3.20 (m, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₄H₁₇N₂O₄BrCl₂: 546.0; Found: 547.0 (M+H).

Example 832-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetamide

¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 0.6H), 10.65 (s, 0.4H), 7.77 (m,1H), 7.71 (m, 1H), 7.56 (m, 1H), 7.52-7.45 (m, 3H), 7.38-7.07 (m, 4H),6.91 (d, J=8.4 Hz, 1H), 6.64-6.55 (m, 1H), 6.41 (s, 0.6H), 5.51 (s,0.4H), 4.96 (s, 0.6H), 4.70 (s, 0.4H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₃H₁₆N₃O₃ICl₂: 579.0; Found: 580.1(M+H).

Example 84[7-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 0.8H), 10.61 (s, 0.2H), 7.52 (m,1H) 7.46-7.39 (m, 4H), 7.32 (m, 2H), 7.15 (d, J=9.0 Hz, 2H), 6.97 (m,1H), 6.86 (d, J=8.4 Hz, 0.6H), 6.78 (d, J=8.4 Hz, 0.4H), 6.28 (s, 0.4H),6.23 (s, 0.6H), 5.72 (br s, 0.4H), 5.23 (s, 0.6H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₃H₁₅N₂O₄Cl₃: 488.0; Found: 489.0(M+H).

Example 85(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 0.6H), 10.37 (s, 0.4H), 7.50 (d,J=8.4 Hz, 1H), 7.41-7.29 (m, 4H), 7.17-7.00 (m, 4H), 6.91 (m, 1H), 6.72(d, J=8.4 Hz, 0.6H), 6.64 (d, J=8.4 Hz, 0.4H), 6.34 (s, 0.4H), 6.25 (s,0.61), 5.71 (s, 0.4H), 5.25 (s, 0.6H), 2.14 (s, 2H), 2.12 (s, 1H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₈N₂O₄Cl₂: 468.1; Found:469.0(M+H).

Example 86(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-naphtho[2,3-e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 0.6H), 10.64 (s, 0.4H), 8.21 (s,0.6H), 8.17 (s, 0.4H), 7.88 (m, 3H), 7.69 (m, 1H) 7.55 (d, J=8.4 Hz,1H), 7.49-7.39 (m, 4H), 7.29 (s, 1H), 7.21 (m, 1H), 7.01 (m, 2H), 6.41(s, 0.4H), 6.32 (s, 0.6H), 5.81 (s, 0.4H), 5.32 (s, 0.6H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₇H₁₈N₂O₄Cl₂: 504.1; Found: 505.0(M+H).

Example 87[8-Chloro-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 0.8H), 10.58 (s, 0.2H), 7.52 (m,2H), 7.40 (m, 1H), 7.14 (m, 4H), 7.00 (m, 1H), 6.91 (m, 3H), 6.30 (s,0.2H), 6.25 (s, 0.8H) 5.76 (s, 0.2H), 5.22 (s, 0.8H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₃H₁₅N₂O₄Cl₃: 488.0; Found: 489.0(M+H).

Example 88(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethynyl-2,5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 0.5H), 10.66 (s, 0.5H), 7.52 (m,2H) 7.43-7.29 (m, 4H), 7.15 (m, 3H), 6.96 (m, 1H), 6.83 (d, J=8.4 Hz,0.6H), 6.75 (d, J=8.4 Hz, 0.4H), 6.29 (s, 0.4H), 6.23 (s, 0.6H), 5.74(br s, 0.4H), 5.21 (s, 0.6H), 4.16 (s, 0.6H), 4.14 (s, 0.4H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₆N₂O₄ICl₂: 478.0; Found:479.0(M+H).

Example 89[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-1,4yl]-p-tolyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 0.8H), 10.46 (s, 0.2H), 7.81 (s,1H), 7.50 (m, 2H), 7.36 (d, J=7.9 Hz, 2H), 7.20 (m, 1H), 7.08 (m, 3H),6.81 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 6.27 (s, 1H), 5.83 (brs, 0.2H), 5.16 (s, 0.8H), 2.22 (s, 3H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₄H₁₈N₂O₄ICl: 560.0; Found: 561.0(M+H).

Example 90(4-Chloro-3-fluoro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 0.9H), 10.60 (s, 0.1H), 7.79 (s,1H), 7.52 (m, 3H), 7.35 (m, 2H), 7.13 (m, 2H), 6.95 (d, J=8.0 Hz, 1H),6.63 (d, J=8.6 Hz, 1H), 6.29 (s, 0.1H), 6.14 (s, 0.9H), 5.80 (s, 0.1H).5.29 (s, 0.9H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₃H₁₄N₂O₄ICl₂F: 597.9; Found: 598.9(M+H).

Example 91[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(2-fluoro-4-trifluoromethyl-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (br s, 1H), 7.80 (s, 1H), 7.74-7.53(m, 5H), 7.12 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.1 Hz, 1H), 6.63 (d, J=8.6Hz, 1H), 6.45 (s, 1H), 5.60 (s, 0.1H), 5.24 (s, 0.9H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₄H₁₄N₂O₄IClF₄: 632.0; Found: 633.0(M+H).

Example 92(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 0.8H), 10.32 (s, 0.2H), 7.52 (d,J=8.4 Hz, 1H), 7.36 (m, 3H), 7.17-7.03 (m, 4H), 6.83 (d, J=8.0 Hz, 1H),6.63 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.37 (s, 0.2H), 6.29 (m,0.8H), 5.74 (s, 0.2H), 5.26 (s, 0.8H), 2.42 (m, 2H), 1.00 (m, 3H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₅H₂₀N₂O₄Cl₂: 482.1; Found:483.1(M+H).

Example 93(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.49 (s, 0.8H), 10.27 (s, 0.2H), 7.53 (d,J=8.4 Hz, 1H) 7.36 (m, 2H) 7.17-7.03 (m, 3H), 6.98 (d, J=8.4 Hz, 1H),6.78 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.38 (s, 0.2H), 6.31 (m,0.8H), 5.76 (s, 0.2H), 5.29 (s, 0.8H), 2.72 (m, 1H), 1.02 (m, 6H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₅H₂₀N₂O₄Cl₂: 496.1; Found:497.1(M+H).

Example 94[7-tert-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.45 (s, 0.8H), 10.25 (s, 0.2H), 7.52 (d,J=8.4 Hz, 1H), 7.44 (m, 1H), 7.40-7.31 (m, 3H), 7.22-7.03 (m, 3H), 6.98(d, J=8.6 H, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 6.37(s, 0.2H), 6.29 (m, 0.8H), 5.75 (s, 0.2H), 5.27 (s, 0.8H), 1.13 (s, 8H),1.11 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₂₄N₂O₄Cl₂:510.1; Found: 511.1(M+H).

Example 95[3-(4-Chloro-phenyl)-7-ethyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 1H), 7.48 (d, J=7.0 Hz, 1H), 7.35(m, 6H), 7.09 (d, J=8.6 Hz, 2H), 6.92 (d, J=8.1 Hz, 2H), 6.74 (d, J=8.1Hz, 1H), 6.32 (s, 1H), 5.12 (s, 1H), 2.43 (q, J=7.7 Hz, 2H), 1.00 (t,J=7.5 Hz, 3H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₅H₂₁N₂O₄Cl₂:448.1; Found: 449.1(M+H).

Example 96[3-(4-Chloro-phenyl)-7-isopropyl-2,5-dioxo-2,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 7.48 (d, J=7.0 Hz, 2H),7.35(m, 3H), 7.07 (m, 3H), 6.91 (d, J=8.4 Hz, 2H), 6.73 (d, J=8.4 Hz,2H), 6.31 (s, 1H), 5.11 (s, 1H), 2.74 (m, 1H), 1.03 (d, J=7.0 Hz, 6H).Mass spectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₃N₂O₄Cl: 462.1; Found:463.1(M+H).

Example 97[7-tert-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 7.50 (d, J=7.0 Hz, 2H), 7.37(m, 3H), 7.24 (dd, J=2.4, 8.6 Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.90 (d,J=7.9 Hz, 2H), 6.72 (d, J=8.6 Hz, 1H), 6.32 (s, 1H), 5.10 (m, 1H), 1.13(s, 9H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₂₅N₂O₄Cl₂: 476.2;Found: 477.1(M+H).

Example 98[7-sec-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 7.49 (d, J=7.0 Hz, 2H), 7.36(m, 4H), 7.20 (m, 1H), 7.03 (m, 3H), 6.86 (m, 1H), 6.73 (m, 1H), 6.31(s, 1H), 5.11 (s, 1H), 2.45 (m, 1H), 1.44 (m, 1H), 1.28 (m, 1H), 1.06(m, 3H), 0.45 (m, 3H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₇H₂₅N₂O₄Cl: 476.2; Found: 477.1(M+H).

Example 99[7-sec-Butyl-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.44(m, 3H), 7.21-6.99 (m, 5H), 6.71 (m, 1H), 6.19 (s, 1H), 5.23 (s, 1H),2.44 (m, 1H), 1.45 (m, 1H), 1.29 (m, 1H), 1.05 (m, 3H), 0.45 (m, 3H).Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₂₄N₂O₄Cl₂: 510.1; Found:511.1(M+H).

Example 100(4-Bromo-phenyl-3-(4-chloro-phenyl)-7-isopropyl-2,5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 0.7H), 10.34 (s, 0.3H), 7.54 (m,2H), 7.46 (d, J=8.6 Hz, 2H), 7.36-7.24(m, 2H), 7.09 (m, 3H), 6.96 (m,1H), 6.72 (d, J=8.4 Hz, 0.7H), 6.64 (d, J=8.4 Hz, 0.3H), 6.30 (s, 0.3H),6.17 (s, 0.7H), 5.65 (s, 0.3H), 5.24 (s, 0.7H), 2.72 (m, 1H), 1.03 (m,6H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₂N₂O₄ClBr: 540.0; Found:541.0(M+H).

Example 101[3-(4-Bromo-phenyl)-7-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.52 (s, 0.7H), 10.34 (s, 0.3H), 7.52 (d,J=8.4 Hz, 1H), 7.41 (m, 3H), 7.28-7.21(m, 3H), 7.12-7.03 (m, 2H), 6.91(m, 1H), 6.72 (d, J=8.6 Hz, 0.7H), 6.64 (d, J=8.6 Hz, 0.3H), 6.30 (s,0.3H), 6.17 (s, 0.7H), 5.65 (s, 0.3H), 5.24 (s, 0.7H), 2.73 (m, 1H),1.03 (m, 6H). Mass spectrum (LCMS, EST pos) Calcd. for C₂₆H₂₂N₂O₄ClBr:540.0; Found: 541.0(M+H).

Example 102(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-cyclopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 0.7H), 10.35 (s, 0.3H), 7.50 (d,J=8.4 Hz, 1H), 7.39 (m, 2H), 7.21-7.09 (m, 4H), 6.92 (m, 3H), 6.70 (d,J=8.4 Hz, 0.7H), 6.61 (d, J=8.4 Hz, 0.3H), 6.31 (s, 0.3H), 6.22 (s,0.7H), 5.67 (s, 0.3H), 5.23 (s, 0.7H), 1.80 (m, 1H), 0.86 (m, 2H), 0.5(m, 1H), 0.42 (m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₆H₂₀N₂O₄Cl₂: 494.1; Found: 495.0(M+H).

Example 103[3-(4-Chloro-phenyl)-7-cyclopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 0.7H), 10.30 (s, 0.3H), 7.47 (d,J=7.0 Hz, 2H), 7.38-7.08 (m, 5H), 7.04 (d, J=8.6 Hz, 2H), 6.88 (m, 2H),6.70 (d, J=8.4 Hz, 0.7H), 6.61 (d, J=8.4 Hz, 0.3H), 6.34 (br s, 1H),5.71 (s, 0.3H), 5.16 (s, 0.7H), 1.79 (m, 1H), 0.85 (m, 2H), 0.53 (m,1H), 0.44(m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₁N₂O₄Cl:460.1; Found: 461.1(M+H).

Example 104[3-(4-Chloro-3-fluoro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 0.9H), 10.36 (s, 0.1H), 7.50 (m,3H), 7.34 (m, 2H), 7.17 (m, 2H), 7.05-6.80 (m, 3H), 6.37 (s, 1H), 5.19(s, 1H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₄N₂O₄Cl₂F: 597.9;Found: 598.9(M+H).

Example 105(2,5-Dioxo-3-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-phenyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.79 (s, 0.9H), 10.61 (s, 0.1H), 7.77 (s,1H), 7.53 (m, 4H), 7.38 (m, 4H), 7.03 (m, 2H), 6.81 (m, 2H), 6.67 (d,J=8.6 Hz, 0.9H), 6.58 (d, J=8.6 Hz, 0.1H), 6.27 (s, 0.1H), 6.16 (s,0.9H), 5.64 (s, 0.1H), 5.30 (s, 0.9H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₃H₁₈N₂O: 386.1; Found: 387.1(M+H).

Example 106[3-(4-Chlorophenyl)-7-phenyl-2,5-dioxo-1,2,3,5tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 0.8H), 10.50 (s, 0.2H), 7.82 (s,1H), 7.52 (m, 4H), 7.41(m, 2H), 7.33 (m, 5H), 7.02 (d, J=8.2 Hz, 2H),6.91 (d, J=8.3 Hz, 1H), 6.82 (m, 2H), 6.39 (bs, 1H), 5.25 (bs, 1H).

Mass spectrum (LCMS, ESI pos.) Calcd. For C₂₉H₂₁ClN₂O₄: 496.10. Found:497.0 (M+H).

Example 107[3-(4-Chlorophenyl)-7-(4-methylphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.67 (bs, 1H), 7.77 (m, 1H). 7.49 (m, 3H),7.41 (m, 4H), 7.25 (m, 4H), 7.06 (m, 2H), 6.90 (d, J=8.9 Hz, 2H), 6.39(bs, 1H), 5.20 (bs 1H), 2.32 (s, 3H). Mass spectrum (LCMS, ESI pos.)Calcd. For C₃₀H₂₃ClN₂O₄: 510.10. Found: 511.0 (M+H).

Example 108[3-(4-Chlorophenyl)-7-(3-methylphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[c][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (bs, 1H), 7.92 (m, 1H), 7.63 (m, 2H),7.43 (m, 4H), 7.29 (m, 5H), 7.16 (m, 1H), 7.04 (m, 1H), 6.89 (m, 2H),6.53 (bs, 1H), 5.40 (bs, 1H), 2.40 (s, 3H). Mass spectrum (LCMS, ESIpos.) Calcd. For C₃₀H₂₃ClN₂O₄: 510.10. Found: 511.0 (M+H).

Example 109[3-(4-Chlorophenyl)-7-(4-hydroxyphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (bs, 0.85H), 10.56 (s, 0.15H), 9.62(s, 1H), 7.68 (s, 1H), 7.52 (m, 3H), 7.36 (m, 4H), 7.17 (m, 1H), 7.10(m, 2H), 6.97 (d, J=7.7 Hz, 2H), 6.87 (d, J=8.5 H, 2H), 6.81 (d, J=8.6Hz, 2H), 6.37 (bs, 1H), 5.14 (bs, 1H), 2.40. Mass spectrum (LCMS, ESIpos.) Calcd. For C₂₉H₂₁ClN₂O₅: 512.15. Found: 513.1 (M+H).

Example 110[3-(4-Chlorophenyl)-7-(4-hydroxycarbonylphenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 13.1 (bs, 1H), 10.80 (bs, 0.4H), 10.59 (s,0.6H), 7.98 (d, J=6.5 Hz, 2H), 7.85 (d, J=9.5 Hz, 1H), 7.65 (m, 3H),7.50 (d, J=8.0 Hz, 1H), 7.34 (m, 4H), 7.24 (d, J=7.2 Hz, 1H), 7.14 (d,J=8.6 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.94 (m, 1H), 6.37 (d, J=14.8 Hz,1H), 5.76 (s, 1H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₃₀H₂₁ClN₂O₆: 540.16. Found: 541.0 (M+H).

Example 111(4-Chlorophenyl)-[3-(4-chlorophenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]aceticacid

¹H NMR (400 MHz, d₆-DMSO): Major (75%): δ 8.25 (d, J=2.2 Hz, 1H), 7.22(d, J=8.4 Hz, 2H), 7.19 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 7.08 (d, J=8.3 Hz,2H), 6.99 (d, J=8.4 Hz, 2H), 6.93 (br m, 1H), 6.77 (d, J=7.9 Hz, 2H),6.27 (d, J=8.7 Hz, 1H), 6.15 (br s, 1H), 5.02 (s, 1H), 3.89 (br m, 2H).Minor (25%): 7.97 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.36 (d,J=8.5 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.11 (dd, J=8.8 Hz, J=2.2 Hz,2H), 6.93 (br m, 1H), 6.19 (d, J=8.8 Hz, 1H), 6.15 (br s, 1H), 5.23 (s,1H), 3.89 (br m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. ForC₂₃H₁₇Cl₂IN₂O₃: 565.97; found: 566.94 (M+H).

Example 112[3-(4-Chlorophenyl)-2,5-dioxo-8-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, d₆-DMSO): δ10.41 (s, 1H), 7.73-7.61 (m, 1H), 7.57-7.32(m, 8H), 7.28-7.02 (m, 5H), 6.98 (d, J=8.7 Hz, 1H), 6.72 (d, J=7.8 Hz,1H), 6.32 (s, 1H), 5.29 (s, 1H). Mass Spectrum (LCMS, ESI pos.): Calcd.for C₂₉H₂₁ClN₂O₄: 496.12; found: 497.12 (M+H).

Example 113[7-Benzo[1,3]dioxol-5-yl-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[c][1,4]diazepin-4-yl]-phenylaceticacid

¹H NMR (400 MHz, d₆-DMSO): Major (67%): δ 10.84 (s, 1H), 7.65 (d, J=2.1Hz, 1H), 7.56-7.34 (m, 9H), 7.23 (d, J=8.1 Hz, 1H), 7.05 (s, 1H),6.99-6.93 (m, 2H), 6.86 (d, J=8.5 Hz, 1H), 6.37 (s, 1H), 5.20 (s, 1H).Minor (33%): 10.69 (s, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.56-7.34 (m, 9H),7.23 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 6.99-6.93 (m, 2H), 6.81 (d, J=8.3Hz, 1H), 6.34 (s, 1H), 5.40 (s, 1H). Mass Spectrum (LCMS, ESI pos.):Calcd. for C₃₁H₂₁F₃N₂O₆: 574.14; found: 574.98 (M+H).

Example 1143-(4-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (d, J=2.0 Hz, 1H), 7.33 (d, J=8.8 Hz,2H), 7.19-6.96 (m, 4H), 6.75 (d, J=8.8 Hz, 1H), 6.39-6.29 (m, 1H), 6.21(d, J=8.8 Hz, 1H), 4.92 (d, J=5.2 Hz, 1H), 4.08-3.96 (m, 1H), 3.46-3.36(m, 2H), 2.93-2.75 (m, 2H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₉O₂IN₂O₃: 579.98; Found:580.8 (M+H).

Example 1152-[3-(4-Chloro-phenyl)-7-iodo-2,3-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4yl]-3-naphthalen-2-yl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 0.7 H), 10.42 (s, 0.3 H),7.87-7.84 (m, 1.0 H), 7.82-7.68 (m, 3.0 Hz), 7.66-7.62 (m, 0.7 H), 7.58(bs, 0.3 H), 7.55 (d, J=2.0 Hz, 1.0 H), 7.51-7.36 (m, 3.0H), 7.20-7.07(m, 3.0 H), 6.92 (bs, 1.0H), 6.56-6.52 (m, 1.0 H), 5.80 (bs, 0.7 H),5.58 (bs, 0.7H), 5.44 (bs, 0.3H) 5.38 (bs, 0.3H) 3.62-3.08 (m, 2.0H).Mass spectrum (LCMS, ESI pos.) Calcd For C₂₈H₂₀ClIN₂O₄: 610.02 Found:610.94 (M+H).

Example 1162-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-naphthalen-2-yl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 0.7H), 10.44 (s, 0.3H), 7.92-7.55(m, 5.0 H), 7.56-7.36 (m, 4.0H), 7.31-7.19 (bs, 1.0 H), 7.12-6.96 (m,2.0H), 6.93-6.82 (m, 1.0H), 6.58-6.46 (m, 1.0H), 5.80 (bs, 0.7H),5.67-5.57 (m, 0.7H), 5.49 (s, 0.3H), 5.43-5.35 (m, 0.3H), 3.71-3.52 (m,1.0H), 3.21-3.08 (m, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₂₉H₂₀F₃IN₂O₅: 660.04. Found: 660.98 (M+H).

Example 1172-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-naphthalen-1-yl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 0.7H), 10.39 (s, 0.3H), 8.32 (d,J=8.8 Hz, 0.7 H), 8.27-8.15 (m, 0.3H), 7.97-7.83 (m, 1.0H), 7.84-7.73(m, 0.3H), 7.73-7.65 (m, 0.7H), 7.62-7.44 (m, 3.0H), 7.40-7.23 (m,3.0H), 7.22-7.07 (m, 3.0H), 6.64-6.54 (m, 1.0H), 5.87 (bs, 1.0H), 5.62(bs, 1.0H), 5.36 (bs, 0.6H), 5.20 (bs, 0.4H), 3.89-3.52 (m, 2.0H). Massspectrum (LCMS, ESI pos.) Calcd. For C₂₈H₂₀ClIN₂O₄: 610.02. Found:610.92 (M+H).

Example 1182-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-naphthalen-1-yl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 0.7H), 10.40 (s, 0.3H), 8.34 (d,J=8.4 Hz, 0.7H), 8.21 (b, 0.3H), 7.88 (d, J=8.0 Hz, 1.0H), 7.78 (d,J=7.2 Hz, 0.3H), 7.69 (d, J=8.4 Hz, 0.7H), 7.72-7.68 (m, 5.0H),7.67-7.22 (m, 4.0H), 7.07 (d, J=8.4 Hz, 1.0H), 7.04-7.00 (m, 0.3H), 6.58(d, J=8.8 Hz, 0.7H), 5.90 (bs, 0.7H), 5.70-5.63 (m, 0.7H), 5.46-5.37 (m,0.3H), 5.26-5.16 (m, 0.3H), 3.97-3.60 (m, 2.0H). Mass spectrum (LCMS,ESI pos.) Calcd. For C₂₉H₂₀F₃IN₂O₅: 660.04; Found: 660.99(M+H).

Example 119[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e[1,4]diazepin-4-yl]-(4-fluoro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 0.6H), 10.50 (s, 0.4H), 7.80 (d,J=2 Hz, 0.6H), 7.72 (d, J=2.4 Hz, 0.4H), 7.58-7.47 (m, 2.0H), 7.44-7.32(m, 1.0H), 7.25-7.03 (m, 4.0H), 6.87-6.75 (m, 1.0H), 6.64 (d, J=8.4 Hz,0.6H), 6.55 (d, J=8.4 Hz, 0.4H), 6.29 (d, J=6 Hz, 1.0H), 5.80 (s, 0.6H),5.76 (s, 0.4H, 5.22 (1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₂₃H₁₅ClFIN₂O₄: 563.97; Found: 564.84 (M+H).

Example 120(4-Fluoro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 DMSO-d₆): δ 10.63 (s, 0.7H), 10.48 (s, 0.3H), 7.75 (d, J=2Hz, 0.7H), 7.67 (d, J=2 Hz, 0.3H), 7.59-7.46 (m, 2.3H), 7.43-7.36 (m,0.7H), 7.29 (d, J=8.4 Hz, 0.7H), 7.16-7.06 (m, 2.3H), 7.03-6.97 (d,J=8.4 Hz, 1.0H), 6.93-6.87 (d, J=8.4 Hz, 1.0H), 6.63 (d, J=8.8 Hz,0.7H), 6.53 (d, J=8.8 Hz, 0.3H), 6.32 (s, 0.3H), 6.28 (s, 0.7H), 5.83(s, 1.0H), 5.76 (s, 0.3H), 5.25 (s, 0.7H). Mass spectrum (LCMS, ESIpos.) Calcd. For C₂₄H₁₅F₄IN₂O₅: 614.00; Found: 614.94(M+H).

Example 1212-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5tetrahydrobenzo[e][1,4]diazepin-4-yl]-3-(4-iodo-phenyl)-propionicacid

¹H NMR (400 M&z, DMSO-d₆): δ 10.72 (s, 0.8H), 10.49 (s, 0.2H), 7.68 (s,0.4H), 7.60-7.49 (m, 2.6H), 7.49-7.43 (m, 1.0H), 7.27-7.20 (m, 3.0H),7.11-7.04 (m, 3.0H), 7.00 (d, J=8 Hz, 0.2H), 6.53 (d, J=8.8 H, 0.8H),5.73 (s, 1.0H), 5.56-5.45 (m, 0.8H), 5.40 (s, 0.2H), 2.95-2.84 (m,2.0H). Mass spectrum (LCMS, ESI pos.) Calcd. For C₂₅H₁₇F₃I₂N₂O₅: 735.92.Found: 736.83 (M+H).

Example 1223-(4-Bromo-phenyl)-2-[7-iodo-2,5-dioxo-3(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 0.4H), 10.47 (s, 0.6H), 7.69 (d,J=2Hz, 0.6H), 7.48 (d, J=2 Hz, 0.4H), 7.51-7.43 (m, 1.0H), 7.39-7.33 (m,2.0H), 7.29-7.12 (m, 3.0H), 7.09-6.99 (m, 2.0H), 6.60-6.50 (m, 1.0H),5.76 (s, 1.0H), 5.53 (bs, 0.6H), 5.39 (s, 0.4H), 5.10 (bs, 1.0H), 3.17(d, J=5.12 Hz, 2.0H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₂₅H₁₇BrF₃IN₂O₅: 687.93. Found: 688.80 (M+H).

Example 1233-(4-Bromo-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 0.61H), 10.50 (s, 0.4H), 7.73 (d,J=2 Hz, 0.4H), 7.60 (d, J=2 Hz, 0.6H), 7.55-7.45 (m, 1.0H), 7.41-7.32(m, 2.0), 7.25-7.03 (m, 6.0H), 6.55 (d, J=8.4 Hz, 1.0H), 5.70 (s, 0.6H),5.55-5.46 (m, 0.6H), 5.35 (s, 0.4H), 5.10 (bs, 0.4H), 3.20-2.84 (m,2.0H),

Mass spectrum (LCMS, ESI pos.) Calcd. For C₂₄H₁₇BrClIN₂O₄: 637.91.Found: 638.82(M+H).

Example 1242-[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-thiophen-2-yl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 0.7H), 10.59 (s, 0.3H), 7.73 (bs,0.3H), 7.70-7.66 (m, 0.7H), 7.60-7.55 (m, 0.3H), 7.51 (dd, J=2.0 Hz, 8.0Hz, 0.7H), 7.32 (d, J=5.2 Hz, 0.3H), 7.30-7.25 (m, 1.7H), 7.19-7.04 (m,4.0H), 6.92-6.84 (m, 2.0H), 5.69 (s, 0.7H), 5.48-5.41 (m, 1.0H), 5.19(bs, 0.3H), 3.56-3.15 (m, 2.0H). Mass spectrum (LCMS, ESI pos.) Calcd.For C₂₃H₁₆FIN₂O₅S: 615.98. Found: 616.75 (M+H).

Example 125[3-4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-trifluoromethyl-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 0.6H), 10.58 (s, 0.4H), 7.80 (d,J=2.4 Hz, 0.6H), 7.73 (d, J=2.0 Hz, 0.4H), 7.72-7.62 (m, 3.0H),7.58-7.50 (m, 2.0H), 7.18 (s, 2.0H), 7.06 (d, J=8.4 Hz, 1.0H), 6.88-6.82(m, 1.0H), 6.63 (d, J=8.4 Hz, 0.6H), 6.53 (d, J=8.4 Hz, 0.4H), 6.37 (s,0.4H), 6.27 (s, 0.6H), 5.76 (s, 0.4H), 5.28 (s, 0.6H). Mass spectrum(LCMS, ESI pos.) Calcd. For C₂₄H₁₅ClF₂N₂O₄: 613.97. Found: 614.86 (M+H).

Example 1262-[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-thiophen-2-yl-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 0.7H), 10.59 (s, 0.3H), 7.75-7.71(m, 1.0H), 7.70-7.66 (m, 1.0H), 7.60-7.49 (m, 1.0H), 7.32 (d, J=5.2 Hz,0.3H), 7.30-7.25 (m, 0.7H), 7.19-7.03 (m, 3.0H), 6.93-6.84 (m, 1.0H),6.78 (d, J=8.0 Hz, 0.7H), 6.65 (d, J=8.8 Hz, 0.3H), 6.58 (d, J=8.4 Hz,1.0H), 5.57 (s, 0.7H), 5.53-5.47 (m, 0.7H), 5.41 (s, 0.3H), 5.28-5.21(bs, 0.3H), 3.62-3.54 (m, 2.0H). Mass spectrum (LCMS, ESI pos.) Calcd.For C₂₂H₁₆ClIN₂O₄S: 565.96. Found: 566.90 (M+H), 591.32 (M+Na).

Example 127[7-Iodo-2,5-dioxo-3-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-trifluoromethyl-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 0.8H), 10.57 (s, 0.2H), 7.79-7.74(d, J=2.0 Hz, 1.0H), 7.73-7.61 (m, 4.0H), 7.56-7.49 (dd, J=1.6 Hz, 8.4Hz, 1.0H), 7.03-6.92 (m, 3.01H), 6.62 (d, J=8.4 Hz, 2.0H), 6.27 (bs,1.0H), 5.93 (s, 0.4H), 5.38 (s, 0.6H). Mass spectrum (LCMS, ESI pos.)Calcd. For C₂₅H₁₅F₆IN₂O₅: 663.99. Found: 664.89 (M+H).

Example 128(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 0.6H), 10.49 (s, 0.4H), 7.74 (d,J=2.3 Hz, 0.6H), 7.66 (d, J=2.1 Hz, 0.4H), 7.53-7.47 (m, 2.0H),7.38-7.32 (m, 2.0H), 7.28 (d, J=8.8 Hz, 1.0H), 7.09 (d, J=8.8 Hz, 1.0H),7.05-6.88 (m, 3.0H), 6.62 (d, J=8.8 Hz, 0.6H), 6.53 (d, J=9.6 Hz, 0.4H),6.28 (s, 0.4H), 6.20 (s, 0.6H), 5.89 (s, 0.4H), 5.23 (s, 0.6H). Massspectrum (LCMS, ESI pos.) Calcd. For C₂₄H₁₅ClF₃N₂O₅: 629.97. Found:630.89 (M+H).

Example 129(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 0.6H), 10.53 (s, 0.4H), 7.78 (d,J=2.0 Hz, 0.6H), 7.70 (d, J=2.0 Hz, 0.4H), 7.56-7.45 (m, 3.0H),7.43-7.31 (m, 4.0H), 7.10-7.00 (m, 1.0H), 6.62 (d, J=8.8 Hz, 1.0H), 6.52(d, J=8.8 Hz, 0.6H), 6.31 (s, 0.4H), 6.24 (s, 0.6H); 6.02-5.96 (m,0.4H), 5.31-5.25 (m, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₂₄H₁₅ClF₃IN₂O₄: 613.97. Found: 614.86(M+H).

Example 130[3-(4-Bromo-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 0.7H), 10.48 (s, 0.3H), 7.80 (d,J=2.4 Hz, 0.7H), 7.72 (d, J=2.0 Hz, 0.3H), 7.56-7.45 (m, 2.0H),7.40-7.27 (m, 3.0H), 7.25-7.18 (m, 1.0H), 7.15-7.09 (m, 1.0H), 6.77 (m,1.0H), 6.63 (d, J=8.8 Hz, 0.3H), 6.54 (d, J=4.8 Hz, 0.7H), 6.27 (s,0.3H), 6.22 (s, 0.7H). 5.84 (bs, 1.0H), 5.16 (s, 1.0H). Mass spectrum(LCMS, ESI pos.) Calcd. For C₂₃H₁₅BrClIN₂O₄: 623.89. Found: 626.77(M+H).

Example 131[3-(4-Bromo-phenyl)-2,5-dioxo-7-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.67 (s, 0.7H), 10.53 (s, 0.3H), 7.82 (d,J=2.0 Hz, 0.7H), 7.74 (d, J=2.0 Hz, 0.3H), 7.58-7.49 (m, 4.0H),7.47-7.40 (m, 3.0H), 7.38-7.30 (m, 3.0H), 7.29-7.24 (m, 1.0H), 7.21-7.14(m, 2.0H), 6.91 (d, J=8.4 Hz, 1.0H), 6.86-6.79 (m, 1.0H), 6.40 (s,0.3H), 6.34 (s, 0.7H), 5.81 (s, 0.3H), 5.26 (s, 0.7H). Mass spectrum(LCMS, ESI pos.) Calcd. For C₂₉H₂₀BrClN₂O₄: 574.03. Found: 574.90 (M+H).

Example 132(4-Chloro-phenyl)-[2,5-dioxo-7-phenyl-3-(4-trifluoromethyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 0.5H), 10.55 (s, 0.5H), 7.79-7.68(m, 2.0H), 7.58-7.29 (m, 11.0H), 7.16 (bs, 2.0H), 6.94-6.85 (m, 0.5H),6.80 (d, J=8.4 Hz, 0.5H), 6.40 (bs, 0.5H), 6.30 (bs, 0.5H), 5.95 (bs,0.5H), 5.33 (bs, 0.5H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₃₀H₂₀ClF₃N₂O₄: 564.11. Found: 565.02 (M+H).

Example 133(4-Chloro-phenyl)-[2,5-dioxo-7-phenyl-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 0.4H), 10.50 (s, 0.6H), 7.73 (d,J=2.4 Hz, 0.4H), 7.66 (d, J=2.4 Hz, 0.6H), 7.60-7.28 (m, 11.0H), 7.05(d, J=8.4 Hz, 2.0H), 6.99 (s, 1.0H), 6.90 (d, J=8.0 Hz, 0.6H), 6.80 (d,J=8.4 Hz, 0.4H), 6.40 (bs, 0.6H), 6.29 (bs, 0.4H), 5.87 (bs, 0.6H), 5.30(bs, 0.4H). Mass spectrum (LCMS, ESI pos.) Calcd. For C₃₀H₂₀ClF₃N₂O₅:580.10. Found: 581.00 (M+H).

Example 134(4-Chlorophenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-7-phenyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 0.4H), 10.51 (s, 0.6H), 7.81 (d,J=1.6 Hz, 0.4H), 7.73 (d, J=2.4 Hz, 0.6H), 7.59-7.48 (m, 4.0H),7.47-7.30 (m, 5.0H), 7.23 (d, J=8.4 Hz, 1.0H), 7.13. (d, J=8.4 Hz,2.0H), 7.06(d, J=8.8 Hz, 2.0H), 6.91 (d, J=8.0 Hz, 1.0H), 6.82 (d, J=8.4Hz, 1.0H), 6.39 (bs, 0.6H), 6.33 (bs, 0.4H), 5.84 (bs, 0.4H), 5.27 (bs,0.6H). Mass spectrum (LCMS, ESI pos.) Calcd For C₂₉H₂₀Cl₂N₂O₄: 530.08.Found: 531.01(M+H).

Example 135[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-thiophen-2-yl-aceticacid

¹H NMR (400 MHz, DMSO-d₄): δ 10.62 (s, 0.8H), 10.52 (s, 0.2H), 7.80 (d,J=2.4 Hz, 0.8H), 7.73 (d, J=2.4 Hz, 0.21H), 7.56-7.51 (m, 1.0H), 7.37(d, J=8.4 Hz, 1.0H), 7.19-7.15 (m, 1.0H), 7.10 (d, J=8.6 Hz, 2.0H),6.95-6.91 (m, 1.0H), 6.80 (d, J=8.4 Hz, 2.0H), 6.65 (d, J=8.6 Hz, 0.8H),6.58 (d, J=8.4 Hz, 0.2H), 6.44 (bs, 0.6H), 5.85 (bs, 0.4H), 5.50 (bs,1.0H).

Mass spectrum (LCMS, ESI pos.) Calcd. For C₂₁H₁₄ClIN₂O₄S: 551.94. Found:552.83 (M+H).

Example 136[7-Iodo-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-thiophen-2-yl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 0.8H), 10.52 (s, 0.2H), 7.74 (d,2.0 Hz, 0.8H), 7.68 (d, J=2.0 Hz, 0.2H), 7.55-7.49 (m, 1.0H), 7.42-7.37(m, 1.0H), 7.28 (d, J=8.4 Hz, 0.2H), 7.20 (d, J=2.8 Hz, 0.8H), 7.13-6.99(m, 2.0H), 6.96-6.87 (m, 3.0H), 6.64 (d, J=8.8 Hz, 0.8H), 6.56 (d, J=8.8Hz, 0.2H), 6.44 (bs, 0.8), 5.88 (bs, 0.2H), 5.55 (bs, 1.0H). Massspectrum (LCMS, ESI pos.) Calcd. For C₂₂H₁₄F₂N₂O₅S: 601.96. Found:602.81(M+H).

Example 137(3-Biphenyl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-(4chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 0.7H), 10.52 (s, 0.3H), 7.82 (d,J=2.0 Hz, 0.7H), 7.74 (d, J=2.4 Hz, 0.3H), 7.57-7.22 (m, 12.0H), 6.86(d, J=7.6 Hz, 2.0H), 6.66 (d, J=7.6 Hz, 0.7H), 6.56 (d, J=8.8 Hz, 0.3H),6.33 (bs, 0.7H), 5.95 (bs, 0.3H), 5.29 (bs, 1.0H). Mass spectrum (LCMS,ESI pos.) Calcd. For C₂₉H₂₀ClIN₂O₄: 622.02. Found: 622.91 (M+H).

Example 138[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-ethyl-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 0.8H), 10.51 (s, 0.2H), 7.79 (d,J=2.0 Hz, 0.8H), 7.73 (d, J=2.0 Hz, 0.2H), 7.56-7.49 (m, 1.0H), 7.39 (d,J=8.0 Hz, 2.0H), 7.29-7.15 (m, 1.0H), 7.12 (d, J=8.0 Hz, 2.0H), 7.06 (d,J=8.4 Hz, 1.0H), 6.77 (d, J=8.0 Hz, 2.0), 6.64 (d, J=8.4 Hz, 0.8H), 6.55(d, J=8.8 Hz, 0.2H), 6.30 (bs, 1.0H), 5.82 (bs, 0.2H), 5.21 (bs, 0.8H),2.62-2.51 (m, 2.0H), 1.21-1.14 (m, 3.0H). Mass spectrum (LCMS, ESI pos.)Calcd. For C₂₅H₂₀ClIN₂O₄: 574.02. Found: 574.94 (M+H).

Example 139[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(3,4-dichloro-phenyl)aceticacid

¹H NMR (400 DMSO-d₆): δ 10.70 (s, 0.6H), 10.64 (s, 0.4H), 7.79 (d, J=2.0Hz, 1.0H), 7.81-7.78 (m, 1.0H), 7.61-7.46 (m, 2.0H), 7.40-7.31 (m,1.0H), 7.18 (s, 1.0H), 7.13 (d, J=8.4 Hz, 1.0H), 7.04-7.00 (m, 1.0H),6.63 (d, J=8.4 Hz, 1.0H), 6.56 (d, J=8.8 Hz, 0.6H), 6.29 (bs, 0.4H),6.12 (bs, 0.6H), 5.80 (bs, 0.4H), 5.32 (bs, 1.0H). Mass spectrum (LCMS,ESI pos.) Calcd. For C₂₃H₁₄Cl₃IN₂O₄: 613.91. Found: 614.84 (M+H).

Example 140(2-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 0.2H), 10.55 (s, 0.8H), 7.77 (d,J=2.4 Hz, 1.0H), 7.60-7.49 (m, 2.0H), 7.44-7.30 (m, 4.0H), 7.16 (d,J=8.8 Hz, 1.0H), 7.11 (d, J=8.4 Hz, 0.2H), 6.89 (d, J=8.0 Hz, 0.8H),6.61 (d, J=8.8 Hz, 1.0H), 6.55 (d, J=8.8 Hz, 1.0H), 6.29 (bs, 1.0H),5.23 (bs, 0.8H), 5.10 (bs, 0.2H). Mass spectrum (LCMS, ESI pos.) Calcd.For C₂₃H₁₅Cl₂IN₂O₄: 579.95. Found: 580.92 (M+H).

Example 141(4-tert-Butyl-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 0.7H), 10.55 (s, 0.3H), 7.77 (d,J=2.0 Hz, 0.7H), 7.75-7.67 (m, 0.3H), 7.55-7.48 (m, 1.0H), 7.39 (d,J=8.4 Hz, 2.0H), 7.29 (d, J=8.4 Hz, 2.0H), 7.25-7.14 (m, 1.0H), 7.02 (d,J=8.0 Hz, 2.0H), 6.92 (d, J=8.0 Hz, 0.3H), 6.73-6.62 (m, 3.0H), 6.54 (d,J=8.4 Hz, 0.7H), 6.27 (s, 1.0H), 5.92 (bs, 0.3H), 5.27 (bs, 0.7H), 1.27(s, 1.0H), 1.20 (s, 9.0H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₂₇H₂₄ClIN₂O₄: 602.05. Found: 602.99 (M+H).

Example 142[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-4-isopropyl-phenyl)aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 0.8H), 10.54 (s, 0.2H), 7.79 (d,J=2.0 Hz, 0.8H), 7.73 (d, J=2.0 Hz, 0.2H), 7.57-7.50 (m, 1.0H), 7.39 (d,J=8.0 Hz, 2.0H), 7.27 (d, J=8.0 Hz, 0.8H), 7.21 (d, J=8.4 Hz, 0.2H),7.14 (d, J=8.0 Hz, 2.0H), 7.03 (d, J=8.4 Hz, 2.0H), 6.72 (d, J=8.8 Hz,1.0H), 6.65 (d, J=8.8 Hz, 1.0H), 6.54 (d, J=8.8 Hz, 0.2H), 6.30 (bs,0.8H), 5.86 (s, 0.2H), 5.27 (bs, 0.8H), 2.88-2.76 (m, 1.0H), 1.18 (d,J=8.8 Hz, 1.2H), 1.11 (d, J=6.8 Hz, 6.0H). Mass spectrum (LCMS, ESIpos.) Calcd. For C₂₆H₂₂ClIN₂O₄: 588.03. Found: 588.95 (M+H).

Example 143(3-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 0.7H). 10.60 (s, 0.3H), 7.80 (d,J=2.0 Hz, 0.7H), 7.73 (d, J=2.4 Hz 0.3H), 7.57-7.50 (m, 2.0H), 7.49-7.44(m, 0.7H), 7.41 (s, 0.3H), 7.35-7.29 (m, 3.0H), 7.18 (s, 1.0H), 6.92 (d,J=8.0 Hz, 2.0H), 6.63 (d, J=8.8 Hz, 0.7H), 6.56 (d, J=8.4 Hz, 0.3H),6.31 (bs, 0.3H), 6.23 (bs, 0.7H), 5.84 (bs, 0.3H), 5.26 (bs, 0.7H). Massspectrum (LCMS, ESI pos.) Calcd. For C₂₃H₁₅Cl₂IN₂O₄: 579.95. Found:581.00 (M+H).

Example 144[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-trifluoromethoxy-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 0.8H), 10.59 (s, 0.2H), 7.80 (d,J=2.0 Hz, 0.8H), 7.74 (d, J=2.0 Hz, 0.2H), 7.61 (d, J=8.8 Hz, 2.0H),7.57-7.48 (m, 2.0H), 7.28 (d, J=8.4 Hz, 2.0H), 7.18 (s, 1.0H), 7.07 (d,J=8.4 Hz, 1.0H), 6.85-6.12 (m, 1.0H), 6.65 (d, J=8.4 Hz, 0.8H), 6.55 (d,J=8.4 Hz, 0.2H), 6.35 (bs, 0.2H), 6.31 (bs, 0.8H), 5.77 (bs, 0.2H), 5.31(bs, 0.8H). Mass spectrum (LCMS, ESI pos.) Calcd. For C₂₄H₁₅ClF₃IN₂O₅:629.97. Found: 630.95 (M+H).

Example 145(4-Bromo-phenyl)-[3-(4-chlorophenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 0.7), 10.56 (s, 0.3H), 7.79 (d,J=2.0 Hz, 0.7H), 7.73 (d, J=2.0 Hz, 0.3H), 7.58-7.41(m, 5.0H), 7.32 (d,J=8.4 Hz, 1.0H), 7.23 (s, 1.0H), 7.11 (d, J=8.8 Hz, 1.0H), 6.94-6.85 (m,1.0H), 6.64 (d, J=8.4 Hz, 0.7H), 6.55 (d, J=8.0 Hz, 0.3H), 6.29 (bs,0.3H), 6.23 (bs, 0.7H), 5.78 (bs, 0.3H), 5.23 (bs, 0.7H). Mass (LCMS,ESI pos.) Calcd. For C₂₁H₁₅BrClN₂O₄: 623.89. Found: 624.90 (M+H).

Example 146[3-(4-Chlorophenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[c][1,4]diazepin-4-yl]-(3-hydroxy-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1.0H), 9.50, (s, 1.0H), 7.78 (d,J=2.0 Hz, 1.0H), 7.54 (dd, J=2.0 Hz, 8.0 Hz, 1.0H), 7.08 (d, J=8.4 Hz,3.0H), 6.91 (s, 2.0H), 6.84-6.76 (m, 2.0H), 6.69-6.59 (m, 2.0H), 6.26(bs, 1.0H), 5.24 (bs, 1.0H). Mass spectrum (LCMS, ESI pos.) Calcd. ForC₂₃H₁₆ClIN₂O₅: 561.98. Found: 562.89 (M+H).

Example 147[3-(4-Chlorophenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-hydroxy-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 0.7H), 10.43 (s, 0.3H), 9.43 (s,0.7H), 9.38 (s, 0.3H) 7.76 (d, J=2.4 Hz, 1.0H), 7.70 (d, J=1.6 Hz,0.3H), 7.50 (m, 0.7H), 7.25 (d, J=8.4 Hz, 2.0H), 7.23-7.11 (m, 3.0H),7.07 (d, J=2.4 Hz, 1.0H), 6.83-6.76 (m, 1.0H), 6.68-6.60 (m, 2.0H), 6.22(bs, 1.0H), 6.17 (b, 0.3H), 5.14 (bs, 0.7H). Mass spectrum (MS, ESIpos.) Calcd. For C₂₃H₁₆ClIN₂O₅: 561.98. Found: 562.80 (M+H).

Example 148(4-Chloro-phenyl)-[3-(4-chloro-3-trifluoromethyl-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 0.6H), 10.63 (s, 0.4H), 7.76-7.69(m, 1.0H), 7.61-7.44 (m, 3.0H), 7.40 (s, 1.0H), 7.36-7.21 (m, 1.0H),7.17 (d, J=8.0 Hz, 1.0H), 6.67-6.51 (m, 2.0H), 6.38-6.19 (m, 1.0H), 5.63(bs, 0.4H), 5.50 (bs, 0.6H), 5.17 (bs, 1.0H). Mass spectrum (LCMS, ESIpos.) Calcd. For C₂₄H₁₄Cl₂F₃IN₄: 647.93. Found: 648.91(M+H).

Example 149[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-cyclohexyl-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.99 (s, 1.0H), 7.74 (d, J=1.6 Hz, 1.0H),7.57 (dd, J=2.0 Hz, 8.4 Hz, 1.0H), 7.22 (d, J=8.8 Hz, 2.0H), 6.96 (d,J=8.4 Hz, 2.0H), 6.62 (d, J=8.8 Hz, 1.0H), 5.90 (bs, 1.0H), 5.17-5.10(m, 1.0H), 1.89-0.87 (m, 11.0H). Mass spectrum (LCMS, ESI pos.) Calcd.For C₂₃H₂₂ClIN₂O₄: 552.03. Found: 552.90 (M+H).

Example 150(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-8-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 0.4H), 10.51 (s, 0.6H), 7.93 (s,0.4H), 7.85 (s, 0.6H), 7.50 (d, J=8.8 Hz, 1.0H), 7.41-7.31 (m, 3.0H),7.18 (s, 2.0H), 7.09 (d, J=8.8 Hz, 1.0H), 6.86-6.81 (m, 0.6H), 6.77 (s,0.4H), 6.68 (s, 1.0H), 6.35-6.27 (m, 1.0H), 5.78 (bs, 0.6H), 5.25 (bs,0.4H) 2.18 (s, 1.8H), 2.17 (s, 12H). Mass spectrum (LCMS, ESI pos.)Calcd. For C₂₄H₁₇Cl₂IN₂O₄: 593.96 (M+H). Found: 594.89.

Example 151[3-(4-Chloro-phenyl)-7,8-difluoro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.6-7.7 (m, 2H), 7.4-7.5 (m, 1H), 7.2-7.4(m, 4H), 6.9-7.0 (m, 2H), 6.6-6.8 (m, 4H), 5.7 (s, 0.13H), 5.4 (s,0.87H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₅ClF₂N₂O₄: 456.1;Found: 457.0 (M+H).

Example 152[7,8-Difluoro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.6 (m, 2H), 7.2-7.5 (m, 5H), 6.6-6.9 (m,6H), 5.8 (s, 0.1H), 5.4 (s, 0.9H). (LCMS, ESI pos) Calcd. forC₂₄H₁₅F₅N₂O₅: 506.1; Found: 507.1 (M+H).

Example 153[3-(4-Chloro-phenyl)-7-fluoro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.6-7.7 (m, 2H), 7.2-7.4 (m, 5H), 6.9-7.1(m, 2H), 6.6-6.9 (m, 6H), 5.7 (m, 0.1H), 5.4-5.5 (s, 0.9H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₆ClFN₂O₄: 438.1; Found: 439.0(M+H).

Example 154[7-Fluoro-2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.6-7.7 (m, 2H), 7.4-7.5 (m, 1H), 7.2-7.4(m, 5H), 6.9-7.0 (m, 2H), 6.6-6.9 (m, 7H), 5.7 (s, 0.2H), 5.5 (s,0.8H).). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₆F₄N₂O₅: 488.1;Found: 489.1 (M+H).

Example 155[7-Acetylamino-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.4-7.9 (m, 5H), 7.0-7.3 (m, 3H), 6.6-6.9(m, 7H), 5.4-5.8 (m, 1H), 1.9-2.2 (s, 3H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₅H₂₀ClN₃O₅: 477.1; Found: 478.0 (M+H).

Example 156[7-Acetylamino--2,5-dioxo-3-(4-trifluoromethoxy-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.6-7.9 (m, 3H), 7.2-7.5 (m, 5H), 6.6-6.9(m, 6H), 5.7 (br s, 1H), 1.9-2.2 (s, 1H). (LCMS, ESI pos) Calcd. forC₂₆H₂₀F₃N₃O₆: 527.1; Found: 528.1 (M+H).

Example 157[3-(4-Chloro-phenyl)-7-(3-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.8-7.9 (s, 1H), 7.6-7.7 (n, 2H), 7.2-7.5(m, 8H), 6.8-6.9 (m, 3H), 6.7-6.8 (m, 3H), 5.4 (s, 1H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₉H₂₀Cl₂N₂O₄: 530.1; Found: 531.0 (M+H).

Example 158[3-(4-Chloro-phenyl)-7-(4-methyl-thiophen-2-yl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.8 (s, 1H), 7.6-7.7 (s, 1H), 7.4-7.5 (m,5H), 7.2-7.4 (m, 2H), 6.6-6.9 (m, 5H), 5.7 (s, 0.4H), 5.4-5.5 (s, 0.6H),2.2 (3 H, s). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₈H₂₁ClN₂O₄S:516.1; Found: 517.0 (M+H).

Example 159[3-(4-Chloro-phenyl)-2,5-dioxo-7-thiophen-3-yl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.9 (s, 1H), 7.6 (s, 1H), 7.4-7.55 (m, 4H),7.2-7.4 (m, 5H), 7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 6.7-6.8 (m, 2H). 5.7(s, 0.5H), 5.4 (s, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₇H₁₉ClN₂O₄S: 502.1; Found: 503.0 (M+H).

Example 160[3-(4-Chloro-phenyl)-7-furan-3-yl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]phenyl-aceticacid methyl ester

¹H-NMR (400 MHz, DMSO-d₆): δ 7.9 (s, 1H), 7.8 (s, 1H), 7.4-7.7 (m, 8H),7.0-7.3 (s, 3H), 6.7-6.9 (m, 3H), 5.3 (s, 0.4H), 5.2 (s, 0.6H), 3.8 (s,3H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₈H₂₁ClN₂O₅: 500.0; Found:501.0 (M+H).

Example 161[3-(4-Chloro-phenyl)-7-furan-3-yl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.8-7.9 (m, 2H), 7.6-7.7 (m, 1H), 7.2-7.5(m, 7H), 7.0-7.1 (m, 1H), 6.6-6.9 (m, 5H), 5.7 (s, 0.4H), 5.5 (m, 0.6H).

Mass spectrum (LCMS, ESI pos) Calcd for C₂₇H₁₉ClN₂O₅: 486.1; Found:487.0 (M+H).

Example 162[3,7-Bis-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid methyl ester

¹H-NMR (400 MHz, DMSO-d₆): δ 7.8-7.9 (s, 1H), 7.4-7.7 (m, 11H), 7.1-7.2(m, 1H), 6.8-7.0 (m, 4H), 6.7 (m, 1H), 5.3 (s, 0.18H), 5.25 (s, 0.82H),3.8 (s, 3H). Mass spectrum (LCMS, ESI pos) Calcd for C₃₀H₂₂Cl₂N₂O₄:544.1; Found: 545.0 (M+H).

Example 163[3,7-Bis-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.8-7.9 (m, 1H), 7.6-7.7 (m, 1H), 7.4-7.5(m, 4H), 7.2-7.4 (m, 6H), 7.0-7.1 (m, 1H), 6.7-6.9 (m, 4H), 5.7 (s,0.5H), 5.45 (s, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₉H₂₀Cl₂N₂O₄: 530.1; Found: 531.0 (M+H).

Example 164[7-(3Amino-phenyl)-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 7.8-7.9 (m, 1H), 7.6-7.7 (s, 1H), 7.2-7.5(m, 5H), 7.0-7.1 (m, 4H), 6.5-6.9 (m, 6H), 5.7 (s, 0.4H), 5.5 (br s,0.6H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₉H₂₂ClN₃O₄: 511.1;Found: 512.1 (M+H).

Example 165[3-(4-Chloro-phenyl)-7-(3-isopropyl-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-phenyl-aceticacid

¹H-NMR (400 DMSO-d₆): δ 7.8-7.9 (m, 1H), 7.6-7.7 (m, 1H), 7.4-7.5 (m,3H), 7.2-7.4 (m, 6H), 7.0-7.1 (m, 1H), 6.6-6.9 (m, 5H), 5.7 (s, 0.3H),5.5 (s, 0.7H), 2.9-3.0 (m, 1H), 1.2-1.3 (m, 6H). Mass spectrum (LCMS,ESI pos) Calcd. for C₃₂H₂₇ClN₂O₄: 538.2; Found: 539.1 (M+H).

Example 166(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-5-oxo-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H-NMR (400 MHz, DMSO-d₆): δ 12.3-12.5 (br s, 1H), 7.7-7.8 (m, 1H),7.5-7.6 (m, 2H), 7.2-7.4 (m, 6H), 7.1-7.2 (m, 2H), 6.6-6.8 (m, 1H), 6.4(s, 0.7H), 6.2 (s, 0.7H), 5.7 (m, 0.6H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₃H₁₅Cl₂IN₂O₃S: 595.9; Found: 596.9 (M+H).

Example 167(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-7-vinyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): 10.67 (s, 0.6H), 10.52 (s, 0.4H), 7.54-7.36(m, 6H), 7.19-7.05 (m, 3H), 6.95 (m, 1H), 6.82 (d, J=8.4 Hz 0.6H), 6.72(d, J=8.4 Hz, 0.4H), 6.64-6.55 (m, 1H), 6.32 (br s, 0.6H), 6.25 (br s,0.4H), 5.73 (brs, 0.4H), 5.70-5.66 (m, 1H), 5.26 (s, 0.6H), 5.19-5.16(n, 1H). Mass spectrum (LCMS, ESI pos) Calcd for C₂₅H₁₈N₂O₄Cl₂: 480.06;Found: 481.07(M+H).

Example 168(4-Chloro-phenyl)-[3-4-chloro-phenyl)-7-cyano-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]aceticacid

¹H NMR (400 MHz, DMSO-d₆): 11.13 (s, 0.7H), 10.97 (s, 0.3H), 7.88 (m,1H), 7.68 (m, 1H), 7.50-7.41 (m, 4H), 7.17 (m, 3H), 7.01 (m, 2H), 6.28(br s, 0.3H), 6.27 (br s, 0.7H), 5.70 (brs, 0.3H), 5.25 (s, 0.7H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₅N₃O₄Cl₂: 479.04; Found:479.9(M+H).

Example 169[3-(1-Chloro-cuban-4-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chlorophenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): 10.64 (s, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.86(dd, J=8.4 Hz and J=2.2 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 6.88 (d, J=8.7 Hz, 1H), 4.62 (s, 1H), 4.16 (s, 1H), 3.80-3.73(m, 3H), 3.70-3.64 (m, 3H). Mass spectrum (LCMS, ESI pos.): Calcd forC₂₅H₁₇Cl₂IN₂O₄: 605.96; found: 606.99 (M+H).

Example 1703-(4-Chloro-phenyl)-4-[1(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one

¹H NMR (400 MHz, CDCl₃): 7.50 (br s, 1H), 7.45 (dd, J=8.3 Hz and J=2.0Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.12 (d, J=1.9 Hz, 1H), 6.49 (d, J=8.3Hz, 1H), 5.14 (s, 1H), 4.08-4.00 (m, 1H), 3.95-3.85 (m, 2H), 3.89 (d,J=14.9 Hz, 1H), 3.58 (d, J=14.8 Hz, 1H), 2.02-1.99 (m, 1H). Massspectrum (LCMS, ESI pos.): Calcd. for C₂₃H₁₉Cl₂IN₂O₂: 551.99; found:552.90 (M+H).

Example 1713-(4-chloro-phenyl)-4-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one

¹H NMR (400 MHz, CDCl₃): 8.52(d, J=2.1 Hz, 1H), 7.36 (dd, J=8.6 Hz andJ=2.2 Hz, 1H), 7.20-7.14 (m, 4H), 7.08 (d, J=8.5 H, 2H), 6.81 (d, J=8.4Hz, 2H), 6.18 (d, J=8.6 Hz, 1H), 5.48-5.45 (m, 1H), 4.73 (d, J=6.0 Hz,1H), 4.47-4.40 (m, 1H), 4.33-4.24 (m, 1H), 4.22-4.15 (m, 1H), 3.83-3.75(m, 1H), 3.71-3.64 (m, 1H), 3.14-3.08 (m, 1H). Mass spectrum (LCMS, ESIpos.): Calcd. for C₂₃H₁₉Cl₂IN₂O₂: 551.99; found: 552.8 (M+H).

Example 1723-(4-Chlorophenyl)-4-(2-hydroxy-1-phenyl-ethyl)-7-iodo-3,4-dihydro-1H-benzo[e][1,4]diazepin-2,5-dione

¹H NMR (400 MHz, DMSO-d₆): 10.82 (br s, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.5(dd, J=8.5 Hz and J=2.1 Hz, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.40-7.26 (m,3H), 7.03 (d, J=8.6 Hz, 2H), 6.64-6.58 (m, 3H), 6.13-6.05 (m, 1H), 5.17(s, 1H), 5.05 (t, J=5.0 Hz, 1H), 4.11-3.97 (m, 2H). Mass spectrum (LCMS,ESI pos.): Calcd. for C₂₃H₁₈ClIN₂O₃: 532.01; found: 532.95 (M+H).

Example 1733-(4-Chloro-phenyl)-4-(3-hydroxy-1-phenyl-propyl)-7-iodo-3,4-hydroxy-1H-benzo[c][1,4]diazepin-2,5-dione

¹H NMR (400 MHz, DMSO-d₆): 10.94 (s, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.59(d, J=7.3, 2H), 7.54 (dd, J=8.5 Hz and J=2.1 Hz, 1H), 7.37 (t, J=7.4 Hz,2H), 7.30 (t, J=7.3 Hz, 1H), 6.99 (d, J=8.6 Hz, 2H), 6.64 (d, J=8.5 Hz,1H), 6.45 (d, J=8.7 Hz, 2H), 6.33 (t, J=7.7 Hz, 1H), 5.25 (s, 1H), 4.61(t, J=4.9 Hz, 1H), 3.48-3.39 (m, 2H), 2.28-2.20 (m, 2H). Mass spectrum(LCMS, ESI pos.): Calcd. for C₂₄H₂₀ClIN₂O₃: 546.02; found: 546.91 (M+H).

Example 1742-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-2-hydroxy-ethyl)-acetamide

¹H NMR (400 MHz, DMSO-d₆): 10.73 (s, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.78(d, J=2.1 Hz, 1H), 7.56 (dd, J=8.5 Hz and J=2.1 Hz, 1H), 7.50-7.43 (m,4H), 7.13 (d, J=8.6 Hz, 2H), 6.91 (d, J=7.8 Hz, 2H), 6.64 (d, J=8.5 Hz,1H), 6.48 (s, 1H), 5.00 (s, 1H), 4.65 (t, J=5.3 Hz, 1H), 3.42-3.37 (m,2H), 3.29-3.05 (m, 2H). Mass spectrum (LCMS, ESI pos.): Calcd. forC₂₅H₂₀Cl₂IN₃O₄: 622.99; found: 623.75 (M+H).

Example 1753-(4-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-2,5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ10.90 (s, 1H), 7.81 (d, J=2.4 Hz, 1H), 7.64(d, J=8.4 Hz, 2H), 7.56 (dd, J=8.0 Hz, 2.0Hz, 1H), 7.41 (d, J=8.4 Hz,2H), 7.05 (d, J=8.4 Hz, 2H), 6.61 (d, J=8.4 Hz, 1H), 6.54 (d, J=8.8 Hz,2H), 6.42 (t, J=8.0 Hz, 1H), 5.31 (s, 1H), 3.15 (d, J=7.2 Hz, 1). Massspectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₇Cl₂IN₂O₄: 593.96; Found:594.90 (M+H).

Example 176[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(6-chloro-pyridin-3-yl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 0.7H), 10.61 (s, 0.3H), 8.46 (d,J=2.4 Hz, 0.7H), 8.34 (d, J=2.4 Hz, 0.3H), 7.93-7.90 (m, 0.7H),7.81-7.80 (m, 0.3H), 7.78 (d, J=2 Hz, 0.7H), 7.71 (d, J=2.4 Hz, 0.3H),7.54-7.51 (m, 1H), 7.46-7.41 (m, 1H), 7.19-7.13 (m, 2.6H), 7.04-7.02 (m,1.4H), 6.62 (d, J=8.8 Hz, 0.7H), 6.56 (d, J=8.8 Hz, 0.3H), 6.25 (s,0.3H), 6.04 (s, 0.7H), 5.81 (s, 0.3H), 5.40 (s, 0.7H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₂H₁₄Cl₂IN₃O₄: 580.94; Found: 581.93 (M+H).

Example 1772-(4-Chlorophenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-hydroxy-acetamide

¹H NMR (400 MHz, DMSO-d₆): δ10.83 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.76(dd, J=8.0 Hz, 2.0 Hz, 1H), 7.52-7.45 (m, 3H), 7.20 (d, J=8.8 Hz, 2H),7.07 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.20 (s, 1H), 5.24 (s,1H). Mass spectrum (LCMS, ESI neg) Calcd. for C₂₃H₁₆Cl₂IN₃O₄: 594.96;Found: 578.9.

Example 178[7-Bromo-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.50(d, J=8.4 Hz, 2H), 7.44-7.39 (m, 3H), 7.10 (d, J=8.8 Hz, 2H), 6.93-6.85(m, 2H), 6.78 (d, J=8.8 Hz, 1H), 6.24 (s, 1H), 5.22 (s, 1H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₅BrCl₂N₂O₄: 531.96; Found532.90 (M+H).

Example 179[8-Chloro-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e]1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 7.98 (s, 1H), 7.49 (d, J=8.4Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.04 (s, 1H),6.82 (d J=8.4 Hz, 2H), 6.26 (s, 1H), 5.21 (s, 1H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₃H₁₄Cl₃IN₂O₄: 613.91; Found: 614.8 (M+H).

Example 1802-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-methyl-butyricacid

¹H NMR (400 MHz, DMSO-d₆): δ10.80-10.69 (m, 1H), 8.58-8.47 (m, 1H),7.62-7.29 (m, 3H), 7.25-6.83 (m, 5H), 6.80-6.50 (m, 2H), 5.04 (s, 0.5H),4.86 (s, 0.5H), 4.27-4.08 (m, 1H), 2.07-1.97 (m, 1H), 0.92-0.81 (m, 6H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₈H₂₄Cl₂IN₃O₅: 679.01; Found679.66 (M+H).

Example 1813-(4-Chloro-phenyl)-3-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]propionicacid

¹H NMR (400 MHz, DMSO-d₆): δ10.88 (s, 1H), 7.80 (d, J=2.4 Hz, 1H),7.59-7.50 (m, 3H), 7.35 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H).6.64-6.58 (m, 3H), 6.42-6.36 (m, 1H), 5.10 (s, 1H) 2.95-2.86 (m, 1H),2.41-2.34 (m, 1H).

Example 1825-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-pentanoicacid

¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 10.72 (s, 1H), 8.25 (t,J=5.6 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.50-7.41 (m,4H), 7.13 (dd, J=8.0 Hz, 2.0 Hz, 2H), 6.90 (dd, J=8.0 Hz, 1.2 Hz, 2H),6.64 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 4.98 (s, 1H), 3.22-2.98 (m, 2H),2.23-2.17 (m, 2H), 1.52-1.34 (m, 4H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₈H₂₄Cl₂IN₃O₅: 679.01; Found: 679.86 (M+H).

Example 1833-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}acetylamino}-propionicacid

¹H NMR (400 MHz, DMSO-₆): δ 10.73 (s, 1H), 8.37-8.28 (m, 1H), 7.77 (d,J=2.0 Hz, 1H), 7.58-7.53 (m, 1H), 7.46-7.42 (m, 4H), 7.13 (d, J=8.4 Hz,2H), 6.91 (d, J=8.4 Hz, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.43 (s, 1H), 4.97(s, 1H), 3.17 (d, J=5.6 Hz, 2H), 2.42-2.38 (m, 2H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₆H₂₀Cl₂IN₃O₅: 650.98; Found: 651.68 (M+H).

Example 184(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-trifluoromethylsulfanyl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₅ClF₃IN₂O₄S: 645.94;Found: 646.96 (M+H).

Example 185(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-2,5-dioxo-7-(1H-pyrrol-3-yl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 10.60 (s, 1H), 7.66-7.35 (m,6H), 7.22-7.03 (m, 5H), 6.79-6.72 (m, 2H), 6.34-6.28 (m, 1H), 6.21 (s,1H), 5.25 (s, 1H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₁₉Cl₂N₃O₄: 519.08; Found520.00 (M+H).

Example 1863-[4-[Carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl]-propionicacid

¹H NMR (400 MHz, CD₃OD-d₆): δ 8.06-7.89 (m, 1.2H), 7.83 (d, J=8.4 Hz,0.6H), 7.74-7.68 (m, 0.6H), 7.56 (d, J=8.0 Hz, 1H), 7.47-7.24 (m, 3H),7.08-6.93 (m, 2H), 6.82-6.57 (m, 2H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₆H₁₉Cl₂IN₂O₆: 651.97; Found: 652.90 (M+H).

Example 1876-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-hexanoicacid

¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 10.72 (s, 1H), 8.29-8.15 (m,1H), 7.77 (d, J=2.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.51-7.42 (m, 4H), 7.13(d, J=8.8 Hz, 2H), 6.91 (d, J=7.6 Hz, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.41(s, 1H), 4.98 (s, 1H), 3.20-2.95 (m, 2H), 2.16 (t, J=7.6 Hz, 2H),1.53-1.31 (m, 4H), 1.26-1.15 (m, 2H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₉H₂₆Cl₂IN₃O₅: 693.03; Found: 693.82 (M+H).

Example 188[1-(2-tert-Butoxycarbonylamino-ethyl)-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetahydro-benzo[e][1,4]diazepin-4-yl]-4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, CD₃OD): δ 7.94 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.4 Hz,2H), 7.47 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 6.93 (d,J=8.8 Hz, 2H), 6.73 (dd, J=8.0 Hz, 1.6 Hz, 2H), 6.61 (d, J=8.4 Hz, 1H),6.50 (s, 1H), 5.27 (s, 1H), 3.55-3.49 (m, 2H), 3.50-3.45 (m, 1H),3.15-3.10 (m, 1H). Mass spectrum (LCMS, ESI pos) Calcd. forC₃₀H₂₈Cl₂N₃O₆: 723.04; Found: 723.70 (M+H).

Example 189(4-Chloro-phenyl)-{7-iodo-2,5-dioxo-3-[5-(3-trifluoromethl-phenyl)furan-2-yl]-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin4-yl}-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ8.03 (s, 1H), 7.68-7.56 (m, 4H), 7.57-7.44(m, 4H), 7.40-733 (m, 2H), 6.79 (d, J=8.4 Hz,1H), 6.73 (s, 1H 6.48 (d,J=3.2 Hz, 1H), 5.61-5.57 (m, 1H),: 5.49 (s, 1H). Mass spectrum (LCMS,ESI pos) Calcd. for C₂₈H₁₇ClF₃IN₂O₅: 679.98; Found: 680.77 (M+H).

Example 190(4-(Chloro-phenyl)-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1-(2-pyridin-2-yl-ethyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

Mass spectrum (LCMS, ESI pos) Calcd. for C₃₀H₂₂Cl₂IN₃O₄: 685.00; Found:686.18 (M+H).

Example 191(4-Chlorophenyl)-[3-(4-chloro-phenyl)-7-iodo-1-methylcarbamoylmethyl-2,5dioxo-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl]-acetic acid

¹H NMR (400 MHz, DMSO-d₆): δ7.84-7.81 (m, 1H), 7.52-7.46 (m, 3H),7.33-7.27 (m, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.69(d, J=8.8 Hz, 2H), 6.57 (s, 1H), 5.33 (s, 1H), 4.50 (m, 1H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₀Cl₂IN₃O₅: 650.98; Found:651.94 (M+H).

Example 192(4-Chloro-phenyl)-[3-(4-difluoromethoxy-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.93 (d, J=2.0 Hz, 0.6H), 7.89 (d, J=2.0 Hz,0.4H), 7.59 (d, J=8.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.45 (d, J=8.4 Hz,0.6H), 7.37-7.30 (m, 2.4H), 7.13-7.05 (m, 0.4H), 6.85 (d, J=8.4 Hz,0.6H), 6.82-6.70 (m, 2.3H), 6.68-6.65 (m, 0.6H), 6.64-6.58 (m, 1H), 5.70(s, 0.3H), 5.37 (s, 1H). Mass spectrum (LCMS, ESI pos) Calcd forC₂₄H₁₆ClF₂IN₂O₅: 611.98; Found: 612.80 (M+H).

Example 193[1-(2-tert-Butoxycarbonylamino-ethyl)3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.84 (d, J=2.0 Hz, 1H), 7.57-7.45 (m, 3H),7.37 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 7.00 (d, J=8.8 Hz, 2H),6.82 (d, J=8.8 Hz, 1H), 6.56 (s, 1H), 5.76 (s, 1H), 4.11-3.98 (m, 1H),3.78-3.65 (m, 1H), 3.16-3.08 (m, 2H), 1.39 (s, 9H). Mass spectrum (LCMS,ESI pos) Calcd. for C₃₀H₂₈Cl₂IN₃O₆: 723.04; Found: 745.90 (M+Na)

Example 194(3-Benzofuran-2-yl-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-(4-chloro-phenyl)-aceticacid

¹H NMR (400 MHz, CD₃OD): δ8.01 (d, J=1.6 Hz, 1H), 7.64 (d, J=8.8 Hz,2H), 7.58-7.51 (m, 1H), 7.49-7.44 (m, 1H), 7.40-7.32 (m, 2H), 7.26-6.95(m, 4H), 6.83-6.72 (m, 1H), 5.92 (s, 0.7H), 5.80 (s, 0.3H), 5.64, (s0.3H), 5.56 (s, 0.7H). Mass spectrum (LCMS, ESI pos) Calcd forC₂₅H₁₆ClIN₂O₅: 585.98; Found: 586.93 (M+H)

Example 195(4-Chloro-phenyl)-[3-(4chloro-phenyl)-7-iodo-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.84 (d, J=2.0 Hz, 1H), 7.62-7.54 (m, 3H),7.34 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H),6.68 (dd, J=8.8 Hz, 1.2 Hz, 2H), 6.53 (s, 1H), 5.38 (s, 1H), 3.44 (s,3H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₇Cl₂IN₂O₄: 593.96;Found 594.95 (M+H).

Example 196(4-Chloro-phenyl)-[3-(4-cyano-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.91 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.4 Hz,1H), 7.55-7.42 (m, 3H), 739-7.27 (m, 3H), 6.98 (d, J=8.4 Hz, 1H), 6.65(d, J=7.6 Hz, 1H), 6.59 (d, J=8.4 Hz, 0.5H), 6.51 (d, J=8.8 Hz, 0.5H),5.77 (s, 0.5H), 5.44 (s, 0.5H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₅ClIN₃O₄: 570.98; Found:571.80 (M+H).

Example 197[1-Carboxymethyl-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid methyl ester

¹H NMR (400 MHz, DMSO-d₆): δ7.73-6.75 (m, 11H), 6.24 (s, 1H), 5.42 (s,1H), 4.53-4.25 (m, 1H), 4.16-3.86 (m, 1H), 3.78 (s, 3H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₆H₁₉Cl₂IN₂O₆: 651.97; Found: 652.87 (M+H).

Example 198(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-(2-hydroxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ10.46 (s, 1H), 7.62-7.26 (m, 4H), 7.08-6.96(m, 3H), 6.82-6.66 (m, 3H), 6.30 (s, 1H), 5.29 (s, 1H), 4.59 (s, 1H),3.45-3.39 (m, 2H), 2.55 (t, J=8.8 Hz, 2H). Mass spectrum (LCMS, ESI pos)Calcd. for C₂₅H₂₀Cl₂N₂O₅: 498.07; Found: 498.95 (M+H).

Example 199(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-1-(2(R),3-dihydroxy-propyl)-7-iodo-2,5-dioxo1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₁Cl₂IN₂O₆: 653.98; Found654.81 (M+H).

Example 200(4-Chloro-phenyl)-[3-(6-chloro-pyridin-3-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.63-7.57 (m, 2H), 7.30 (d, J=8.4 Hz, 2H),7.00-6.89 (m, 3H), 6.78-6.65 (m, 4H), 5.41 (s, 1H).

Example 201(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-7-hydroxymethyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ10.52 (s, 1H), 7.57-7.42 (m, 2H), 7.41-7.23(m, 3H), 7.22-6.96 (m, 4H), 6.87-6.67 (m, 3H), 6.33 (s, 1H), 5.18 (s,1H), 4.38-4.27 (m, 2H).

Mass spectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₈Cl₂N₂O₅: 484.06; Found485.00 (M+H).

Example 202(4-Chloro-phenyl)-{7-iodo-2,5-dioxo-3-[4-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.96 (d, J=2.0 Hz, 0.4H), 7.80 (d, J=2.0Hz,0.6H), 7.54-7.47 (m, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.29-7.12 (m, 5H),7.06 (d, J=8.4 Hz, 2H), 6.85 (t, J=8.0 Hz, 1.8H), 6.62 (s, 0.7H), 5.96(s, 0.6H), 5.79 (s, 0.4H), 5.36-5.28 (m, 1H). Mass spectrum (LCMS, ESIpos) Calcd. for C₂₅H₁₆ClF₄IN₂O₅: 661.97; Found: 662.90 (M+H).

Example 203(4-Chloro-phenyl)-[7-iodo-3-(4-methylsulfanyl-phenyl)-2,5-dioxo-1,2,3,5-tetahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.92 (s, 0.7H), 7.88 (s, 0.3H), 7.58 (d, J=8.0Hz, 1H), 7.56-7.41 (m, 1.7H), 7.38=7.29 (m, 1.71H), 7.20 (d, J=8.0 Hz0.7H), 7.08 (d, J=8.0 _(Hz), 0.3H), 7.02-6.89 (m, 1H), 6.86-6.69 (m,1H), 6.70-6.63 (m, 1.3H), 6.60 (d, J=8.8 Hz, 0.7H), 6.51 (d, J=8.8 Hz,0.3H), 5.70 (s, 0.3H), 5.35 (s, 0.7H), 2.34 (s, 1H), 2.29 (s, 2H). Massspectrum (LCMS, ESI pos) Calcd. for C₂₄H₁₈ClIN₂O₄S: 591.97; Found:592.90 (M+H).

Example 204(4-Chloro-phenyl)-[7-iodo-2,5-dioxo-3-(4-pyrrolidin-1-yl-phenyl)-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ8.18-8.08 (m, 1H), 7.98-7.85 (m, 1H), 7.59 (d,J=1.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.39-7.28 (n, 3H), 7.06 (d, J=8.0 Hz,1H, 6.74-6.45 (m, 1H), 6.29 (d, J=8.4 Hz, 1H), 6.09 (dd, J=8.0 Hz, 1.2Hz, 1H), 5.66 (s, 0.5H), 5.₃₆ (s, 0.5H), 3.17-3.02 (m, 4H), 1.99-1.87(m, 4H). Mass spectrum LCMS, ESI pos) Calcd. for C₂₇H₂₃ClIN₃O₄: 615.04;Found: 616.07 (M+H).

Example 2052-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N,N-bis-2-hydroxy-ethyl)-acetamide

¹H NMR (400 MHz, DMSO-d₆): δ8.65 (s, 0.5H), 8.20 (s, 0.5H, 8.00 (d,J=1.6 Hz, 0.5H), 7.94 (d, J=2.0 Hz, 0.5H), 7.52-7.42 (m,2.5H), 7.37 (d,J=8.8 Hz, 1H), 7.24 (dd, J=5.6 Hz, 1h), 7.10-6.99 (m, 2H); 6.95 (s, 1H),6.85 (d, J=8.0 Hz, 0.5H), 6.46-6.35 (m, 1H), 5.32 (s, 0.5H), 5.12 (s,0.5H), 4.04-3.06 (m, 8H). Mass spectrum, ESI pos) Calcd. forC₂₇H₂₄Cl₂IN₃O₅: 667.01; Found: 667.85 (M+H).

Example 206(4-Chloro-phenyl)-{7-iodo-2,5-dioxo-3-[4-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl)-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.83-7.74(m, 0.7H), 7.60 (d, J=8.4 Hz, 0.6H),7.52-7.45 (m, 0.7H), 7.42-7.30 (m, 2H), 7.27 (d, J=8.4Hz, 1H), 7.17 (d,J=7.6 Hz, 2H), 7.09-6.97 (m, 3H), 6.89-6.78 (m, 2H), 6.63 (s, 0.6H),6.46 (s, 0.4H), 5.97 (s, 0.5H), 5.60-5.51 (m, 0.6H), 5.37-5.27 (m,0.7H), 4.66-4.58 (m, 0.5H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₅H₁₆ClF₄IN₂O₅: 661.97; Found: 662.89 (M+H).

Example 207[3-(4-Chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4-diazepin-4-yl](6-methyl-pyridin-3-yl)aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ10.76 (s, 1H), 8.53 (d, J=2.0 Hz, 1H),7.78-7.72 (m, 2H), 7.60-7.53 (m, 1H), 7.26-7.16 (m, 3H), 7.10-7.03 (m,2H), 6.65 (d, J=8.8 Hz, 1H), 6.16 (s, 1H), 5.33 (s, 1H), 2.42 (s, 3H).Mass spectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₇ClIN₃O₄: 561.00, Found:562.01 (M+H).

Example 2083-{2-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-propionicacid methyl ester

¹H NMR (400 MHz, DMSO-d₆): δ10.74 (s, 1H), 8.35 (t, J=6.0 Hz, 1H), 7.77(d, J=2.0 Hz, 1H), 7.61-7.51 (m, 1H), 7.45 (s, 2H), 7.13 (d, J=8.4 Hz,2H), 6.91 (d, J=7.8 Hz 2H), 6.64 (d, J=7.8 Hz, 1H), 6.42 (s, 1H), 4.98(s, 1H), 3.56 (s, 3H), 3.48-3.36 (m, 1H), 3.31-3.21 (m, 1H), 2.48-2.40.(m, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₇H₂₂Cl₂IN₃O₅:665.00, Found 665.70 (M+H).

Example 209[7-Amino-3-(4-chloro-phenyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-(4-chloro-phenyl)-aceticacid

¹H NMR (400 Mz DMSO-d₆): δ12.00 (s, 1H), 10.20 (s, 1H), 7.53-7.35 (m,3H), 7.27 (d, J=8.4 Hz, 0.4H), 7.19-6.96 (m, 2.8H), 6.88-6.66 (m, 1.2H0,6.54-6.39 (m, 1.4H), 6.10 (s, 0.7H), 5.18 (s, 0.8H), 5.00 (s, 1.0H),4.42 (s, 0.4H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₃H₁₇Cl₂N₃O₄:469.06; Found: 470.00 (M+H).

Example 2102-(4-Chloro-phenyl)-2-[3-(4-chloro-phenyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-N-(2-hydroxyguanidino-ethyl)-acetamide

¹H NMR (400 MHz, DMSO-d₆): δ10.95 (s, 1H), 10.75 (s, 1H), 8.41 (m, 1H),7.77 (d, J=2.0 Hz, 1H), 7.57 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.53-7.44 (m,3H), 7.14 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.8 Hz,1H), 6.43 (s, 1H), 4.99 (s, 1H), 3.80 (t, J=5.6 Hz, 2H), 3.46-3.36 (m,4H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₆H₂₃Cl₂IN₆O₄: 680.02;Found 681.00 (M+H).

Example 211(4-Chloro-phenyl)-[3-(5-chloro-thiophen-2-yl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydo-benzo[e][1.4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.99-7.89 (m, 1H);,7.67-7.51 (m, 2H),7.44-7.32 (m, 2H), 7.27-6.99 (m, 1H), 6.90-6.82 (m, 0.5H). 6.73 (d, J8.4 Hz, 0.5H), 6.67-6.41 (m, 2H), 6.23-6.18 (m, 0.5H), 5.44-5.38 (m,0.5H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₁H₁₃Cl₂IN₂O₄S: 585.90;Found 586.72 (M+H).

Example 212(4-Chloro-phenyl)-[7-iodo-3-(4-isopropenyl-cyclohex-1-enyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-aceticacid

¹H NMR (400 MHz, DMSO-d₆): δ10.31 (s, 0.8H), 10.15 (s, 0.2H), 7.93-7.78(m, 1H), 7.72-7.64 (m, 1H), 7.44-7.24 (m, 4H), 6.83-6.73 (m, 1H),6.20-6.11 (m, 1H), 5.05-4.93 (m, 1H), 4.57-4.44 (m, 2H), 4.35-4.24 (m,1H), 1.71-1.21 (m, 10H). Mass spectrum (LCMS, ESI pos) Calcd. forC₂₆H₂₄ClIN₂O₄: 590.05; Found: 591.00 (M+H).

Example 213(4-Chloro-phenyl)-[3-(4-chloro-phenyl)-1-(2(S),3-dihydroxy-propyl)-7-iodo-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-aceticacid

¹H NMR (400 MHz, CD₃OD): δ7.87-7.80 (m, 1H), 7.61-7.45 (m, 3H),7.38-7.28 (m, 2H), 7.19-6.91 (m, 4H), 6.80-6.71 (m, 1H), 6.62 (s, 0.3H),5.89 (s, 0.6H), 4.30-3.38 (m, 5H). Mass spectrum (LCMS, ESI pos) Calcd.for C₂₆H₂₁Cl₂IN₂O₆: 653.98; Found: 637.20.

Example 2145-[4-[Carboxy-(4-chloro-phenyl)-methyl]-3-(4-chloro-phenyl)-7-iodo-2,5-dioxo2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl)pentanoicacid

¹H NMR (400 MHz, DMSO-d₆): δ7.97-7.91 (m, 1H), 7.66 (d, J=8.4 Hz, 1H),7.46-7.41 (m, 4H), 7.03 (d, J=8.4 Hz, 2H), 6.73 (d, J=8.4 Hz, 1H), 6.67(s, 1H), 6.64 (d, J=8.4 Hz, 2H), 5.48 (s, 1H), 4.57-4.45 (m, 1H),3.75-3.65 (m, 1H), 2.49-2.39 (m, 2H), 1.75-1.55 (m, 4H). Mass spectrum(LCMS, ESI pos) Calcd. for C₂₈H₂₃Cl₂IN₂O₆: 680.00; Found: 680.85 (M+H).

Example 2155-{3-(4-Chloro-phenyl)-4-[1-4-chloro-phenyl)-2-hydroxy-ethyl]-7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl}-pentanoicacid

¹H NMR (400 MHz, DMSO-d₆): δ7.85 (d, J=2 Hz, 1H), 7.61-7.52 (m, 3H),7.38 (d, J=8.4 Hz, 2H), 6.97-6.87 (m, 3H), 6.58 (dd, J=2.0 Hz, 8.0 Hz,2H), 6.28-6.20 (m, 1H), 5.39 (s, 1H), 4.36-4.24 (m, 2H), 4.20-4.12 (m,1H), 3.83-3.72 (m, 1H), 2.23-2.11 (m, 2H), 1.84-1.65 (m, 2H), 1.64-1.52(m, 2H). Mass spectrum (LCMS, ESI pos) Calcd. for C₂₈H₂₅Cl₂IN₂O₅:666.02; Found: 666.97 (M+H).

Example 2165-{3-(4-Chloro-phenyl)-4-[(4-chloro-phenyl)-diethylcarbamoyl-methyl]-7-iodo-2,5-dioxo-2,3,4,5-tetrahydrobenzo[e][1,4]diazepin-1-yl)-pentanoic acid

¹H NMR (400 MHz DMSO-d₆): δ7.65 (d, J=2.4 Hz 1H), 7.62-7.55 (m, 3H),7.53-7.48 (m, 2H), 7.12-7.06 (m, 2H), 6.94-6.87 (m, 2H), 6.60 (s, 1H),4.89 (s, 1H), 4.24-4.14 (m, 1H), 3.74-3.63 (m, 1H), 3.57-3.47 (m, 2H),3.17-3.08 (m, 2H), 2.23-2.13 (m, 2H), 1.85-1.73 (m, 1H), 1.67-1.58 (m,1H), 1.49-1.40 (m, 2H), 1.10-0.98 (m, 6H). Mass spectrum (LCMS, ESI pos)Calcd. for C₃₂H₃₂Cl₂IN₃O₅: 735.08; Found: 735.82 (M+H).

Example 217 Fluorescent Peptide Assay

The inhibition of MDM2 binding to p53 was measured using a p53 peptideanalogue binding to MDM2 residues 17-125. The published crystalstructure of this complex (Kussie et al., Science 274:948-953 (1996))validates this fragment as containing the p53 binding site, and we havesolved the x-ray structure of the p53 peptide analogue MPRFMDYWEGLN,described to be a peptide inhibitor of the MDM2 p53 interaction (Bottgeret al., J. Mol. Biol. 269-744-756 (1997)). The assay uses N terminalfluorescein RFMDYWEGL peptide (Fl 9mer).

The mdm2 17-125 was produced as a glutathione S transferase fusion asfollows: CDNA encoding residues 17-125 were cloned into pGEX4t-3(Pharmacia) as follows. PCR was performed using ATCC item number 384988containing partial human mdm2 sequence as template and the followingprimers: Forward: 5′-CTC TCT CGG ATC CCA GAT TCC AGC TTC GGA ACA AGA G;Reverse: 5′-TAT ATA TCT CGA GTC AGT TCT CAC TCA CAG ATG TAC CTG AG. ThePCR product was then digested with BamHI and XhoI (sequence recognitionsites underlined in primers), gel purified, and ligated into pGEX4t-3which had also been digested with BamHI and XhoI. Plasmids weretransfected into E. coli X90 strain, grown to an OD of 1.0 in TB 0.2%glucose 100 μg/mL ampicillin and induced with 1 mM IPTG. Cells wereharvested 5 hours post induction, centrifuged, and resuspended in PBS 10mL/g cell paste. Cells were lysed in an Avestin microfluidizer,centrifuged, and the supernatant bound to a glutathione sepharose 4Bresin (Pharmacia). The resin was washed with PBS and the MDM2 17-125cleaved from the GST by the addition of 2 μg/mL thrombin (EnzymeResearch Labs). The cleaved MDM2 was further purified on Sepharose SPFast Flow resin (Pharmacia), eluting with 20 mM 1HEPES pH 7.5 150 mMNaCl. Glutathione was added to 5 mM, and the protein stored at −70° C.

Test compound was incubated for 15 minutes with 30 nM fluorescin peptideFl 9mer and 120 nM MDM2 17-125 in 50 mM HEPES pH 7.5, 150 mM NaCl, 3 mMoctyl glucoside. The polarization of the fluorescein label wasthereafter measured by excitation at 485 nm and emission at 530 nm.Polarization was expressed as a percent of a no compound control, usingbuffer with Fl 9mer but without MDM2 as background.

Compounds of the present invention inhibited the binding of p53 to MDM2.The potency of the compounds was measured as IC₅₀, which is a measure ofthe concentration of the test compound required to inhibit 50% bindingbetween MDM2 and p53. The IC₅₀ values for compounds of the presentinvention ranged from 0.1. μM to >100 μM. Table 1 providesrepresentative data for compounds of the invention. TABLE 1 Inhibitionof MDM2 binding to p53 Example No. IC₅₀ (μM) 1 1.7 4 1.8 10 13 12 56 277.8 32 10.1 39 11.7 46 10.5 56 1.9 74 10 88 0.87 102 1.7 111 0.58 1250.62 130 0.47 145 0.62

Example 218 Tablet Preparation

Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of thecompound of Example 1 (“active compound”) are prepared as illustratedbelow: TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUNDAmount-mg Active compound 25.0 50.0 100.00 Microcrystalline cellulose37.25 100.0 200.0 Modified food corn starch 37.25 4.25 8.5 Magnesiumstearate 0.50 0.75 1.5

All of the active compound, cellulose, and a portion of the corn starchare mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.

Example 219 Intravenous Solution Preparation

An intravenous dosage form of the compound of Example 1 (“activecompound”) is prepared as follows: Active compound 0.5-10.0 mg Sodiumcitrate 5-50 mg Citric acid 1-15 mg Sodium chloride 1-8 mg Water forinjection (USP) q.s. to 1 ml

Utilizing the above quantities, the active compound is dissolved at roomtemperature in a previously prepared solution of sodium chloride, citricacid, and sodium citrate in Water for Injection (USP, see page 1636 ofUnited States Phamacopeial/National Formulary for 1995, published byUnited States Pharmacopeial Convention, Inc., Rockville, Md. (1994).

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

1-35. (canceled)
 36. A pharmaceutical composition, comprising a compoundof Formula I:

or a pharmaceutically acceptable salt thereof; wherein: X and Y areindependently —C(O)—, —CH₂—or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl: or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6. —CH═CH—CH═CH— or—CH₂CH═CHCH₂—; R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl, C₁₋₆ alkoxyphenyl, C₁-6 alkylphenyl, aminophenyl, C₁-6alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆ alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano; R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl: R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl: R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M,—(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) is hydrogen,alkyl, optionally substituted cycloalkyl, or optionally substituted,saturated or partially unsaturated heterocycle; M is a cation; R^(c) andR^(d) are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,aminoalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, and an optionally substituted,saturated or partially unsaturated heterocycle; and n is 0-8, m is 0-8,i is 1-8 and j is 0-8; and (b) one or more pharmaceutically-acceptableexcipients, further comprising: (c) at least one additional substanceselected from the group consisting of synergists, stabilizingsubstances, antineoplastic agents, anticancer agents, and cytostaticagents. 37-42. (canceled)
 43. A method of inhibiting the binding of p53to a protein encoded by hdm2, comprising contacting p53 or one or moreproteins encoded by hdm2, with a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: X and Y areindependently —C(O)—, —CH₂— or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl; or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6, —CH═CH—CH═CH— or—CH₂CH═CHCH₂. R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl, aminophenyl, C₁₋₆alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano: R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl; R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl; R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m),—CO₂M, —(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) ishydrogen, alkyl, optionally substituted cycloalkyl, or optionallysubstituted, saturated or partially unsaturated heterocycle; M is acation: R^(c) and R^(d) are independently hydrogen, alkyl, hydroxyalkyl,carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, and an optionallysubstituted, saturated or partially unsaturated heterocycle; and n is0-8, m is 0-8, i is 1-8 and j is 0-8.
 44. A method of treating acondition that results from the inhibition of one or more functions of acellular protein that induces apoptosis, induces cellular death, orregulates the cell cycle by an HDM2 protein, comprising administering toa patient in need of such treatment a pharmaceutically-effective amountof a compound:

or a pharmaceutically acceptable salt thereof, wherein: X and Y areindependently —C(O)—, —CH₂— or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl; or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6, —CH═CH—CH═CH— or—CH₂CH═CHCH₂—; R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl, C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl, aminophenyl, C₁₋₆alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano; R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl; R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl; R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M,—(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) is hydrogen,alkyl, optionally substituted cycloalkyl, or optionally substituted,saturated or partially unsaturated heterocycle; M is a cation; R^(c) andR^(d) are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,aminoalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, and an optionally substituted,saturated or partially unsaturated heterocycle; and n is 0-8, m is 0-8,i is 1-8 and j is 0-8.
 45. A method of inducing apoptosis, comprisingcontacting an animal with a composition comprising apharmaceutically-effective amount of at least one compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: X and Y areindependently —C(O)—, —CH₂— or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl; or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6, —CH═CH—CH═CH— or—CH₂CH=CHCH₂—; R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl, C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl, aminophenyl, C₁₋₆alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆ alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano; R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl; R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl; R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M,—(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) is hydrogen,alkyl, optionally substituted cycloalkyl, or optionally substituted,saturated or partially unsaturated heterocycle; M is a cation; R^(c) andR^(d) are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,aminoalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, and an optionally substituted,saturated or partially unsaturated heterocycle; and n is 0-8, m is 0-8,i is 1-8 and j is 0-8.
 46. The method according to claim 45, whereinsaid composition further comprises at least onepharmaceutically-acceptable excipient.
 47. A method of preventing ortreating cancer or a condition that results from the uncontrolledproliferation of cells, comprising contacting an animal with (a) acomposition comprising a pharmaceutically-effective amount of anantineoplastic agent, and (b) a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: X and Y areindependently —C(O)—, —CH₂— or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl; or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6. —CH═CH—CH═CH— or—CH₂CH═CHCH₂—; R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkelyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl, aminophenyl, C₁₋₆alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆ alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano; R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl; R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl; R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b) ,—(CH₂)_(m)—CO₂M, —(CH₂)_(i)—or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) ishydrogen, alkyl, optionally substituted cycloalkyl, or optionallysubstituted, saturated or partially unsaturated heterocycle; M is acation; R^(c) and R^(d) are independently hydrogen, alkyl, hydroxyalkyl,carboxyalkyl, aminoalkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, and an optionallysubstituted, saturated or partially unsaturated heterocycle; and n is0-8, m is 0-8, i is 1-8 and j is 0-8.
 48. The method of claim 47,wherein said cancer or condition is selected from the group consistingof breast cancer, ovarian cancer, cervical carcinoma, endometrialcarcinoma, choriocarcinoma, soft tissue sarcomas, osteosarcomas,rhabdomyosarcomas, leiomyomas, leiomyosarcomas, head and neck cancers,lung and bronchogenic carcinomas, brain tumors, neuroblastomas,esophogeal cancer, colorectal adenocarcinomas, bladder cancer,urothelial cancers, leukemia, lymphoma, malignant melanomas, oralsquamous carcinoma, hepatoblastoma, glioblastoma, astrocytoma,medulloblastoma, Ewing's sarcoma, lipoma, liposarcoma, malignantfibroblast histoma, malignant Schwannoma, testicular cancers, thyroidcancers, Wilms' tumor, pancreatic cancers, colorectal adenocarcinoma,tongue carcinoma, gastric carcinoma, and nasopharyngeal cancers.
 49. Themethod of claim 47, wherein said cancer or condition is selected fromthe group consisting of breast cancer, choriocarcinoma, soft tissuesarcomas, osteosarcomas, rhabdomyosarcomas, lipoma and liposarcoma. 50.A method of treating an inflammatory condition, comprising administeringto a patient in need of such treatment a pharmaceutically-effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: X and Y areindependently —C(O)—, —CH₂— or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl; or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6, —CH═CH—CH═CH— or—CH₂CH═CHCH₂—; R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl. C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl, aminophenyl, C₁₋₆alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆ alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano; R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl; R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl; R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M,—(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) is hydrogen,alkyl, optionally substituted cycloalkyl, or optionally substituted,saturated or partially unsaturated heterocycle; M is a cation; R^(c) andR^(d) are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,aminoalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, and an optionally substituted,saturated or partially unsaturated heterocycle; and n is 0-8, m is 0-8,i is 1-8 and j is 0-8.
 51. A method of treating an autoimmune disease orcondition, comprising administering to a patient in need of suchtreatment a pharmaceutically-effective amount of a compound of FormulaI:

or a pharmaceutically acceptable salt thereof; wherein: X and Y areindependently —C(O)—, —CH₂— or —C(S)—; R¹, R³, and R⁴ are independentlyhydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, cyano, amino,alkanoylamino, nitro, hydroxy, carboxy, or alkoxycarbonyl; or R³ and R⁴are taken together to form —(CH₂)_(u)—, where u is 3-6, —CH═CH—CH═CH— or—CH₂CH═CHCH₂—; R² is hydrogen, halo, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, acetylamino, C₁₋₆ alkoxy, phenyl, halophenyl,hydroxyphenyl, C₁₋₆ alkoxyphenyl, C₁₋₆ alkylphenyl, aminophenyl, C₁₋₆alkylenedioxyphenyl, hydroxycarbonylphenyl, thienyl, C₁₋₆ alkylthienyl,furanyl, pyrrolyl, amino, C₁₋₆ hydroxyalkyl or cyano; R⁵ is hydrogen,alkyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl oralkylaminocarbonylalkyl; R⁶ is cycloalkyl, aryl, heteroaryl,cycloalkylalkyl, heteroarylalkyl, or a saturated or partiallyunsaturated heterocycle, each of which is optionally substituted; R⁷ andR⁸ are independently hydrogen or alkyl; R⁹ is cycloalkyl, aryl,heteroaryl, a saturated or partially unsaturated heterocycle,cycloalkyl(alkyl), aralkyl or heteroarylalkyl, each of which isoptionally substituted; and R¹⁰ is —(CH₂)_(n)—CO₂R^(b), —(CH₂)_(m)—CO₂M,—(CH₂)_(i)—OH or —(CH₂)_(j)—CONR^(c)R^(d) where R^(b) is hydrogen,alkyl, optionally substituted cycloalkyl, or optionally substituted,saturated or partially unsaturated heterocycle; M is a cation: R^(c) andR^(d) are independently hydrogen, alkyl, hydroxyalkyl, carboxyalkyl,aminoalkyl, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, and an optionally substituted,saturated or partially unsaturated heterocycle; and n is 0-8, m is 0-8,i is 1-8 and j is 0-8.
 52. The method of claim 51, wherein saidautoimmune disease or condition is selected from the group consisting ofHashimoto's thyroiditis, Grave's disease, multiple sclerosis, perniciousanemia, Addison's disease, insulin-dependent diabetes mellitus,rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), anddermatomyositis, Crohn's disease, Wegener's granulomatosis,Anti-Glomerular Basement Membrane Disease, Antiphospholipid Syndrome,Dermatitis Herpetiformis, Allergic Encephalomyelitis,Glomerulonephritis, Membranous Glomerulonephritis, Goodpasture Syndrome,Lambert-Eaton, Myasthenic Syndrome, Myasthenia Gravis, BullousPemphigoid, Polyendocrinopathies, Reiter's Disease and Stiff-ManSyndrome.
 53. The method of claim 51, wherein said autoimmune disease orcondition is rheumatoid arthritis or systemic lupus erythematosus. 54.The method according to any of claims 43-53, wherein said effectiveamount is between about 1.0 and about 100 milligrams per kilogram perday.